Abca1 elevating compounds

ABSTRACT

The present invention provides compounds useful for increasing cellular ATP binding cassette transporter ABCA1 production in mammals, and to methods of using such compounds in the treatment of coronary artery diseases, dyslipidiemias and metabolic syndrome. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/477,745, filed Jun. 28, 2006, now U.S. patent ______, which claimspriority to U.S. Provisional Patent Application Ser. No. 60/694,741,filed Jun. 28, 2005, the complete disclosures of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds useful for increasingcellular ATP binding cassette transporter ABCA1 production in mammals,and to methods of using such compounds in the treatment of coronaryartery diseases, dyslipidiemias and metabolic syndrome. The inventionalso relates to methods for the preparation of such compounds, and topharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Cholesterol is essential for the growth and viability of higherorganisms. It is a lipid that modulates the fluidity of eukaryoticmembranes, and is the precursor to steroid hormones such asprogesterone, testosterone, and the like. Cholesterol can be obtainedfrom the diet, or synthesized internally in the liver and intestine.Cholesterol is transported in body fluids to tissues by lipoproteins,which are classified according to increasing density. For example, lowdensity lipoprotein cholesterol (LDL) is responsible for transport ofcholesterol to and from the liver and to peripheral tissue cells, whereLDL receptors bind LDL, and mediate its entry into the cell.

Although cholesterol is essential to many biological processes inmammals, elevated serum levels of LDL cholesterol are undesirable, inthat they are known to contribute to the formation of atheroscleroticplaques in arteries throughout the body, which may lead, for example, tothe development of dyslipidemia and coronary artery diseases.Conversely, elevated levels of high density lipoprotein cholesterol(HDL-C) have been found, based upon human clinical data and animal modelsystems, to protect against development of coronary diseases. Low highdensity lipoprotein (HDL) is also a risk factor and marker for thedevelopment of metabolic syndrome and insulin resistance.

In general, excess cholesterol is removed from the body by a pathwayinvolving HDL. Cholesterol is “effluxed” from cells by one of twoprocesses—either by transfer to mature HDL, or an active transfer toapolipoprotein A-1 (Apo A-I). Transfer to mature HDL may involve bothactive and passive transfer mechanism. Transfer to Apo A-I and thegeneration of nascent HDL is mediated by ABCA1. In this process,lipid-poor HDL precursors acquire phospholipid and cholesterol formingnascent HDL which can then converted to mature HDL through the action ofmultiple plasma enzymes and the acquisition of cholesterol fromperipheral tissues. HDL cholesterol is eventually transported to theliver where it is either recycled or excreted as bile. This process isoften referred to as “reverse cholesterol transport”.

One method of treatment aimed at reducing the risk of formation ofatherosclerotic plaques in arteries relates to modifying plasma lipidand lipoprotein levels to desirable levels. Such methods includes dietchanges, and/or treatment with drugs such as derivatives of fibric acid(clofibrate, gemfibrozil, and fenofibrate), nicotinic acid, and HMG-CoAreductase inhibitors, such as mevinolin, mevastatin, pravastatin,simvastatin, fluvastatin, rosuvastatin, and lovastatin, which reduceplasma LDL cholesterol levels by either inhibiting the intracellularsynthesis of cholesterol or inhibiting the uptake via LDL receptors. Inaddition, bile acid-binding resins, such as cholestyramine, colestipoland probucol decrease the level of LDL-cholesterol by reducingintestinal uptake and increasing the catabolism of LDL-cholesterol inthe liver. Nicotinic acid through a poorly defined mechanism increaseHDL levels and decreases triacylglycerol levels.

Another method of reducing the risk of formation of atheroscleroticplaques involves increasing the rate of cholesterol efflux from tissuesand the formation of nascent HDL by increasing ABCA1 gene expression.The nuclear hormone receptor LXR is a key physiologic modulator of ABCA1expression, and effectors of the LXR receptor may be used topharmacologically increase ABCA1 activity. In addition to regulatingABCA1, LXR has been shown to at least partially regulate LXR targetgenes identified in macrophages, liver, intestine and other sites, whichserve to orchestrate a concerted physiological response to excess steroldeposition. These include at least three other members of the ABCtransporter family. Two of which have been identified as agents foranother rare genetic disorder of sterol metabolism termedsitosterolemia. Another has been implicated as potential transporter ofcellular cholesterol to mature and maturing HDL.

Unfortunately, systemic administration of potent full LXR ligands causesincreased plasma triglycerides and liver lipid deposition due to theinduction of several gene products involved in the synthesis of fats.Lipogenic genes in the liver are highly induced by LXR activation eitherdirectly, or via LXR induced transcription of the sterol regulatoryprotein SREBP1c. Selective LXR activation in macrophages, however, mayhave a protective role in reverse cholesterol transport while avoidingthe pitfalls of inducing lipid bio-synthetic genes in the liver.

Additional advantages may be afforded by selectively interfering withthe LXR enhancer/promoter transcription complex with LXR ligands thatincrease transcription of the subset of LXR target genes involved incholesterol transport, but not the lipid bio-synthetic target genes.Tissue selective and/or unique partial LXR agonists may also provide thebeneficial induction of ABCA1 (and other target genes) in macrophagesand other non-hepatic tissues, while causing no or limited induction ofSREBP1c and other lipogenic genes in the liver. See, for example JosephS. B. and Tontonoz, P. (2003) Current Opinion in Pharmacology, 3:192-197 and Brewer H. B. et al. (2004) Arterioscler. Thromb. Vasc.Biol., 24:1755-1760.

It is desired to provide alternative therapies aimed at reducing therisk of formation of atherosclerotic plaques in arteries, especially inindividuals deficient in the removal of cholesterol from artery wallsvia the HDL pathway. HDL cholesterol levels are a steady statemeasurement determined by the relative rates of HDL production and HDLclearance. Multiple enzymes and mechanisms contribute to both productionand clearance. One method of increasing HDL levels would be to increasethe expression of ABCA1 and the generation of nascent HDL resulting inincreased HDL production. Accordingly, it is desired to providecompounds that are stimulators of the expression of ABCA1 in mammalsboth to increase cholesterol efflux and to raise HDL cholesterol levelsin blood. This would be useful for the treatment of various diseasestates and dyslipidemias characterized by low HDL levels, such ascoronary artery disease and metabolic syndrome.

It has also been shown that a combination of a drug that decreases LDLcholesterol levels and a drug that increases HDL cholesterol isbeneficial; see, for example, Arterioscler., Thromb., Vasc. Biol.(2001), 21(8), 1320-1326, by Marian C. Cheung et al. Accordingly, it isalso desired to provide a combination of a compound that stimulates theexpression of ABCA1 with a compound that lowers LDL cholesterol levels.

It should be noted it has also been shown that raising production inmacrophages locally reduces cholesterol deposition in coronary arterieswithout significantly raising plasma HDL cholesterol and withouteffecting cholesterol production by the liver. In this instance, raisingABCA1 expression is beneficial even in the absence of increased HDLcholesterol such that selective non-hepatic upregulation of ABCA1 mayhave beneficial effects on coronary artery disease in the absence ofmeasurable effects on plasma lipid and lipoprotein levels.

SUMMARY OF THE INVENTION

It is an object of this invention to provide compounds capable ofincreasing ABCA1 expression. Accordingly, in a first aspect, theinvention relates to compounds of Formula I:

wherein:

-   R¹ and R² are independently optionally substituted lower alkyl,    optionally substituted aryl, optionally substituted alkenyl,    optionally substituted heteroaryl, or optionally substituted    heterocyclyl; or-   R¹ and R² when taken together with the carbon atom to which they are    attached represent a 5 or 6 membered carbocyclic or heterocyclic    ring;-   R³, R⁴ and R⁵ are independently hydrogen, hydroxyl, optionally    substituted lower alkyl, optionally substituted alkenyl, optionally    substituted alkynyl, optionally substituted lower alkoxy, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted heterocyclyl, cyano, halo, —SO₂—NR⁹R¹⁰, or —C(O)R¹¹, in    which R⁹ and R¹⁰ are independently hydrogen, optionally substituted    lower alkyl, optionally substituted aryl, optionally substituted    heteroaryl, optionally substituted heterocyclyl, or may joint to    form a 5 or 6 membered optionally substituted heterocyclic ring, and    R¹¹ is —OH or optionally substituted lower alkoxy;-   R⁶ is hydrogen, optionally substituted lower alkyl, optionally    substituted cycloalkyl, —C(O)R¹², or —S(O)₂R¹³, in which R¹² is    optionally substituted lower alkyl, lower alkoxy or —NR¹⁴R¹⁵, in    which R¹³, R¹⁴, and R¹⁵ are independently hydrogen, optionally    substituted lower alkyl, optionally substituted aryl, optionally    substituted heteroaryl, or optionally substituted heterocyclyl, or    R¹⁴ and R¹⁵ may join to form a 5 or 6 membered optionally    substituted heterocyclic ring;-   R⁷ is hydrogen, hydroxyl, optionally substituted lower alkyl,    optionally substituted alkenyl, optionally substituted alkynyl,    optionally substituted alkoxy, optionally substituted aryl,    optionally substituted heteroaryl, optionally substituted    heterocyclyl, or —NR¹⁴R¹⁵; and-   R⁸ is hydrogen, cyano, optionally substituted lower alkyl,    optionally substituted heterocyclyl, optionally substituted phenyl,    —C(O)R¹¹, —C(O)R¹⁴, —SR¹³, —OR¹³, —NR⁹S(O)₂R¹⁰, —NR¹⁴C(O)NR¹⁴R¹⁵,    —C(O)NR¹⁴R¹⁵, —CH₂C(O)R¹¹, —S(O)₂R¹³, —B(OH)₂, —C(CF₃)₂OH,    —CH₂P(O)(R¹¹)₂, halo, —NHC(O)R, —N[(CH₂)₂]₂SO₂, or —S(O)₂NR⁹R¹⁰; or-   R⁷ and R⁸ may join together to form an optionally substituted 5 or 6    membered heterocyclic or heteroaryl ring;-   R²⁰ is hydrogen, cyano, hydroxyl, halo, optionally substituted lower    alkyl, optionally substituted alkenyl, optionally substituted    alkynyl, optionally substituted alkoxy, optionally substituted aryl,    optionally substituted heteroaryl, optionally substituted    heterocyclyl, —NR¹⁴R¹⁵, —C(O)R¹¹, —C(O)R¹⁴, —SR¹⁴, —OR¹⁴, —C(S)R¹¹,    C(S)R¹⁴, —NR⁹S(O)₂R¹⁰, —NR¹⁴C(O)NR¹⁴R¹⁴, —C(O)NR¹⁵R¹⁴,    —C(S)NR¹⁵R¹⁴R¹⁵, —CH₂C(O)R¹¹, —S(O)₂R¹³, B(OH)₂, —C(CF₃)₂OH,    —CH₂P(O)(R¹¹)₂, —NHC(O)CH₃, —N[(CH₂)₂]₂SO₂, or —S(O)₂ NR⁹R¹⁰;-   A and D are independently 5 or 6 membered monocyclic heterocyclic,    monocyclic heteroaryl, or monocyclic aryl rings; and-   X is oxygen, sulfur, —S(O)—, —S(O)₂— or —NR¹⁶—, in which R¹⁶ is    hydrogen, optionally substituted lower alkyl, optionally substituted    aryl, —C(O)R¹², or —S(O)₂R¹³.

In a second aspect, the invention relates to a method for using thecompounds of Formula I in the treatment of a disease or condition in amammal that can be treated with a compound that elevates serum levels ofHDL-C, comprising administering to a mammal in need thereof atherapeutically effective dose of a compound of Formula I. Such diseasesinclude, but are not limited to, diseases of the artery, in particularcoronary artery disease, metabolic syndrome and diabetes.

In a third aspect, the invention relates to a method for using thecompounds of Formula I in the treatment of a disease or condition in amammal that can be treated with a compound that promotes cholesterolefflux from cells, comprising administering to a mammal in need thereofa therapeutically effective dose of a compound of Formula I. Suchdiseases include, but are not limited to, diseases of the artery, inparticular coronary artery disease.

In a fourth aspect, the invention relates to a method for using thecompounds of Formula I in the treatment of a disease or conditioncharacterized by low HDL-C in a mammal that can be treated with acompound that elevates serum levels of HDL-C, comprising administeringto a mammal in need thereof a therapeutically effective dose of acompound of Formula I. Such diseases include, but are not limited to,diseases of the artery, in particular coronary artery disease, anddiabetes.

A fifth aspect of this invention relates to pharmaceutical formulations,comprising a therapeutically effective amount of a compound of Formula Iand at least one pharmaceutically acceptable excipient.

A sixth aspect of this invention relates to methods of preparing thecompounds of Formula I.

At present, preferred compounds of the invention include, but are notlimited to:

-   2-(2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((6aS,12aR)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((12aS,6aS)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)acetic    acid;-   2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   methyl    2-bromo-10-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylate;-   1,1,1,3,3,3-hexafluoro-2-(2-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   2-[7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-[(12aS,6aS)-7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;-   3-methylbut-2-enyl    (6aS,12aR)-9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;-   3-methylbut-2-enyl    9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;-   3-methylbut-2-enyl    7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;-   3-methylbut-2-enyl    7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate;-   7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylic    acid;-   3-methylbut-2-enyl    9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate;-   7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylic    acid;-   9-(dihydroxyboramethyl)-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinoline-3-carboxylic    acid;-   1,1,1,3,3,3-hexafluoro-2-(4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   4-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;-   4-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;-   2-(4-ethoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   1,1,1,3,3,3-hexafluoro-2-(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   2-[7,7-dimethyl-4-(3-methylbut-2-enyloxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)acetic    acid;-   3-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)propanoic    acid;-   3-((12aR,6aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)propanoic    acid;-   4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS)-4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   2-((6aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   methyl    (2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}prop-2-enoate;-   (2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}-N,N-dimethylprop-2-enamide;-   (6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}-N,N-dimethylpropanamide;-   methyl    3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl}propanoate;-   4-ethoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1-(4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;-   1-(1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;-   1-methoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   (6aS,12aR)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aS)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (6aS,12aR)-9-fluoro-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylic    acid;-   4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   1,1,1,3,3,3-hexafluoro-2-(4-fluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   ((6aS,12aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-9-fluoro-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-9-ethoxy-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylic    acid;-   10-(1H-1,2,3,4-tetraazol-5-yl)(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   ((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;-   amino(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione;-   {[(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]sulfonyl}methylamine;-   methylethyl    3-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;-   methylethyl    3-(4-methoxy-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinolin-9-yl)benzoate;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-10-carbonitrile;-   2-((6aS,12aR)-1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((6aS,12aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((12aR,6aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2,4-difluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2,4-dichloro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-chloro-4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((6aS,12aR)-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3-thiadiazol-4-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1-methoxy-7,7-dimethyl-9-(4-methyl(1,2,4-triazol-3-yl))-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   2-((12aS,6aR)-4-methoxy-7,7-dimethyl-2-phenyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1-bromo-9-ethoxy-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1-bromo-4-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1-(1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;-   1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   amino(1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione;-   1-bromo-4-methoxy-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-9-bromo-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aS)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   9-(tert-butyl)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   {[(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]sulfonyl}methylamine;-   diethoxy[(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]phosphino-1-one;-   [(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]diethoxyphosphino-1-one;-   4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzenecarbonitrile;-   (12aS,6aS)-1-methoxy-7,7-dimethyl-9-[4-(trifluoromethyl)phenyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aS)-1-methoxy-7,7-dimethyl-9-phenyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-9-ethynyl-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   ethyl    4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;-   4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzenesulfonamide;-   [4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]methan-1-ol;-   (12aS,6aR)-9-(4-fluorophenyl)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1-(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-2-methoxybenzene;-   1-(4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;-   4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS)-4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   4-fluoro-9-(2-methoxyphenyl)-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinolin-12-ol;-   (2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))[(4-methylphenyl)sulfonyl]amine;-   4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoic    acid;-   ethyl    4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;-   4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzamide;-   (12aS,6aR)-9-(4-fluorophenyl)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(2-methyl(1,3-thiazol-4-yl))-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-pyrazol-3-yl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   ethyl    2-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,3-oxazole-4-carboxylate;-   1-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-4-methoxybenzene;-   methyl    3-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;-   3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]propanoic    acid;-   (2E)-3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))phenyl]prop-2-enoic    acid;-   (6aS,12aR)-7-methoxy-13,13-dimethyl-6,13,12a,6a-tetrahydrobenzothiazolo[6,7-b]chromano[3,4-e]pyridine;-   (6aS,12aR)-7-methoxy-13,13-dimethyl-6,13,12a,6a-tetrahydro-1H-chromano[3,4-e]indazolo[6,7-b]pyridine;-   (6aS,12aR)-7-methoxy-2,13,13-trimethyl-6,13,12a,6a-tetrahydrobenzothiazolo[5,4-b]chromano[3,4-e]pyridine;-   (12bS,6aR)-12-methoxy-6,6-dimethyl-6,13,12b,6a-tetrahydrochromano[4,3-b]1,2,5-thiadiazolo[3,4-h]quinoline;-   ethyl    1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylate;-   (6aR,12aS)-6a,7,12,12a-tetrahydro-N-(2-hydroxyethyl)-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide;-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;-   ((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;-   (6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-9-(methylsulfonyl)-6H-chromeno[4,3-b]quinoline;    and-   (6aR,12aS)-9-(4-fluorophenylsulfonyl)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline.-   (6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-N,N,7,7-tetramethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide;-   2-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-ylsulfonyl)acetic    acid;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;-   ((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;-   ((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;-   2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic    acid;-   ((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;-   ((6aS,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;-   ((6aR,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;-   ethyl    1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-1H-pyrazole-4-carboxylate;-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-1H-pyrazole-4-carboxylic    acid;-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide;-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);-   ((6aS,12aS)-4-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone);-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);-   2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone);-   2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone);-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone);-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);-   2-((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic    acid;-   2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone);-   2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone);-   (6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline;-   (6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline;-   (6aR,12aS)-methyl    2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;-   (6aS,12aS)-methyl    2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;-   (6aR,12aS)-methyl    6a,7,12,12a-tetrahydro-1-methoxy-7,7,12-trimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;-   2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetic    acid;-   (6aR,12aS)-6a,7,12,12a-tetrahydro-12-isopropyl-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetic    acid;-   ethyl    2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetate;-   ethyl    2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetate;-   (6aR,12aS)-12-benzyl-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline;-   (6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline;-   (6aR,12aS)-methyl    6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate;-   (6aR,12aS)-methyl    6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5-dimethylisoxazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate;-   (6aS,12aS)-12-ethyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;-   (6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5-dimethylisoxazol-4-yl)-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline.-   (6aR,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aS,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline.-   diethyl    ((6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;-   (6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;-   methyl    3-((6aS,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate;-   methyl    3-((6aR,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate;-   (6aR,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aS,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aR,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aS,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aS,12aS)-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7,12-trimethyl-6H-chromeno[4,3-b]quinoline;    and-   1-((6aS,12aS)-6a,7,12,12a-tetrahydro-2-iodo-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid;-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-2-iodo-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid;-   diethyl    ((6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;-   diethyl    (6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;-   diethyl    ((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;    and-   (6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carbonitrile.

DEFINITIONS AND GENERAL PARAMETERS

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms. This termis exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

The term “substituted alkyl” refers to:

-   1) an alkyl group as defined above, having from 1 to 7 substituents,    for example 1 to 3 substituents, selected from the group consisting    of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,    acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,    azido, cyano, halogen, hydroxy, keto, phosphate, thiocarbonyl,    aminosulfinyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,    heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,    aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,    heterocyclooxy, hydroxyamino, alkoxyamino, phosphate, quaternary    amino, nitro, —SO₃H, —SO-alkyl, —SO-aryl, —SO-heteroaryl,    —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless otherwise    constrained by the definition, all substituents may optionally be    further substituted by 1-3 substituents chosen from alkyl, carboxy,    carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,    substituted amino, quaternary amino, cyano, —SO₃H, and —S(O)_(n)R,    where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or-   2) an alkyl group as defined above that is interrupted by 1-5 atoms    or groups independently chosen from oxygen, sulfur and    —N(R_(a))_(v)—, where v is 1 or 2 and F_(a), is chosen from    hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,    heteroaryl and heterocyclyl. Unless otherwise constrained by the    definition, all substituents may optionally be further substituted    by 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl,    aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted    amino, quaternary amino, cyano, —SO₃H, and —S(O)_(n)R, where R is    alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or-   3) an alkyl group as defined above that has both from 1 to 5    substituents as defined above and is also interrupted by 1-5 atoms    or groups as defined above.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 6 carbon atoms. Groups suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, t-butyl,n-hexyl, and the like exemplify this term.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 7 substituents, for example 1 to 3 substituents, asdefined for substituted alkyl, or a lower alkyl group as defined abovethat is interrupted by 1-5 atoms as defined for substituted alkyl, or alower alkyl group as defined above that has both from 1 to 5substituents as defined above and is also interrupted by 1-5 atoms asdefined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, for example having from 1 to 20 carbonatoms, for example 1-10 carbon atoms, more for example 1-6 carbon atoms.This term is exemplified by groups such as methylene (—CH₂—), ethylene(—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—)and the like.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, for example having from 1 to 6carbon atoms.

The term “substituted alkylene” refers to:

-   (1) an alkylene group as defined above having from 1 to 5    substituents selected from the group consisting of alkyl, alkenyl,    alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,    amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,    hydroxy, keto, phosphate, thiocarbonyl, aminosulfinyl, carboxy,    carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,    alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,    aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,    hydroxyamino, alkoxyamino, quaternary amino, nitro, —SO₃H,    —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and    —SO₂-heteroaryl. Unless otherwise constrained by the definition, all    substituents may optionally be further substituted by 1-3    substituents chosen from alkyl, carboxy, carboxyalkyl,    aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted    amino, quaternary amino, cyano, —SO₃H, and —S(O)_(n)R, where R is    alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or-   (2) an alkylene group as defined above that is interrupted by 1-5    atoms or groups independently chosen from oxygen, sulfur and    —N(R_(a))_(v)—, where v is 1 or 2 and R_(a) is chosen from hydrogen,    alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl,    heterocyclyl carbonyl, carboxyester, carboxyamide and sulfonyl.    Unless otherwise constrained by the definition, all substituents may    optionally be further substituted by 1-3 substituents chosen from    alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,    halogen, CF₃, amino, substituted amino, quaternary amino, cyano,    —SO₃H, and —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n    is 0, 1 or 2; or-   (3) an alkylene group as defined above that has both from 1 to 5    substituents as defined above and is also interrupted by 1-20 atoms    as defined above. Examples of substituted alkylenes are    chloromethylene (—CH(Cl)—), aminoethylene (—CH(NH₂)CH₂—),    methylaminoethylene (—CH(NHMe)CH₂—), 2-carboxypropylene    isomers(—CH₂CH(CO₂H)CH₂—), ethoxyethyl (—CH₂CH₂O—CH₂CH₂—),    ethylmethylaminoethyl    (—CH₂CH₂N(CH₃)CH₂CH₂—),1-ethoxy-2-(2-ethoxy-ethoxy)ethane    (—CH₂CH₂O—CH₂CH₂—OCH₂CH₂—OCH₂CH₂—), and the like.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “alkoxy” refers to the group R—O—, where R is optionallysubstituted alkyl or optionally substituted cycloalkyl, or R is a group—Y-Z, in which Y is optionally substituted alkylene and Z is optionallysubstituted alkenyl, optionally substituted alkynyl; or optionallysubstituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl are as defined herein. Preferred alkoxy groups areoptionally substituted alkyl-O— and include, by way of example, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.

The term “alkylthio” refers to the group R—S—, where R is as defined foralkoxy.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group for example having from 2 to 20 carbonatoms, more for example 2 to 10 carbon atoms and even more for example 2to 6 carbon atoms and having 1-6, for example 1, double bond (vinyl).Preferred alkenyl groups include ethenyl or vinyl (—CH═CH₂), 1-propyleneor allyl (—CH₂CH═CH₂), isopropylene, (—C(CH₃)═CH₂),bicyclo[2.2.1]heptene, and the like. In the event that alkenyl isattached to nitrogen, the double bond cannot be alpha to the nitrogen.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having from 1 to 5 substituents, and for example 1 to 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, quaternary amino,cyano, halogen, hydroxy, keto, phosphate, thiocarbonyl, aminosulfinyl,carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio,thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO₃H, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, quaternary amino, —SO₃H, and —S(O)_(n)R, whereR is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, for example having from 2 to 20 carbon atoms, more forexample 2 to 10 carbon atoms and even more for example 2 to 6 carbonatoms and having at least 1 and for example from 1-6 sites of acetylene(triple bond) unsaturation. Preferred alkynyl groups include ethynyl,(—C≡CH), propargyl (or prop-1-yn-3-yl, —CH₂C≡CH), and the like. In theevent that alkynyl is attached to nitrogen, the triple bond cannot bealpha to the nitrogen.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having from 1 to 5 substituents, and for example 1 to 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, quaternaryamino, halogen, hydroxy, keto, phosphate, thiocarbonyl, aminosulfinyl,carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio,thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO₃H, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, quaternary amino, —SO₃H, and —S(O)_(n)R, whereR is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or whereboth R groups are joined to form a heterocyclic or heteroaryl group(e.g., morpholino). Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, quaternary amino,—SO₃H, and —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0,1 or 2.

The term “aminothiocarbonyl” or “aminosulfinyl” refers to the group—C(S)NRR where each R is independently hydrogen, alkyl, aryl,heteroaryl, heterocyclyl or where both R groups are joined to form aheterocyclic group (e.g., morpholino). Unless otherwise constrained bythe definition, all substituents may optionally be further substitutedby 1-3 substituents chosen from alkyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, quaternary amino, —SO₃H, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “aminosulfonyl” refers to the group —S(O)₂NRR where each R isindependently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or whereboth R groups are joined to form a heterocyclic group (e.g.,morpholino). Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, quaternary amino,—SO₃H, and —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0,1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, quaternary amino, —SO₃H, and —S(O)_(n)R, whereR is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the groups —O(O)C-alkyl, —O(O)C-cycloalkyl,—O(O)C-aryl, —O(O)C-heteroaryl, and —O(O)C-heterocyclyl. Unlessotherwise constrained by the definition, all substituents may beoptionally further substituted by alkyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, quaternary amino, —SO₃H, or —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl oranthryl). Preferred aryls include phenyl, naphthyl and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with from 1 to 5substituents, for example 1 to 3 substituents, selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, quaternary amino, halogen, hydroxy, keto, phosphate,thiocarbonyl, aminothiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO₃H,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1 to 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano,quaternary amino, —SO₃H, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, carboxyalkyl (for example, benzyloxycarbonyl), aryl,heteroaryl and heterocyclyl provided that both R groups are nothydrogen, or a group —Y-Z, in which Y is optionally substituted alkyleneand Z is alkenyl, cycloalkenyl, or alkynyl. Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, quaternary amino, —SO₃H, and —S(O)_(n)R, whereR is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “quaternary amino” refers to the group —NRRR where each R is asdefined for substituted amino. Any two of the R substituents may bejoined to form a heterocyclic group as defined further herein.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl,—C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein,and may be optionally further substituted by alkyl, alkenyl, alkynyl,alkoxy, halogen, CF₃, amino, substituted amino, cyano, quaternary amino,—SO₃H, or —S(O)_(n)R, in which R is alkyl, aryl, or heteroaryl and n is0, 1 or 2.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl,bicyclo[2.2.1]heptane, 1,3,3-trimethylbicyclo[2.2.1]hept-2-yl,(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl), or cyclic alkyl groups towhich is fused an aryl group, for example indane, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups havingfrom 1 to 5 substituents, and for example 1 to 3 substituents, selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, phosphate, thiocarbonyl, aminothiocarbonyl, carboxy, carboxyalkyl,arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,quaternary amino, —SO₃H, —SO-alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1-3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, quaternary amino, —SO₃H, and —S(O)_(n)R, whereR is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “halogen” or “halo” refers to fluoro, bromo, chloro, and iodo.

The term “acyl” denotes a group —C(O)R, in which R is hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl.

The term “heteroaryl” refers to an aromatic group (i.e., unsaturated)comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected fromoxygen, nitrogen and sulfur within at least one ring.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, for example 1 to 3 substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, phosphate,thiocarbonyl, aminothiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,substituted amino, quaternary amino, —SO₃H, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl.

Unless otherwise constrained by the definition, all substituents mayoptionally be further substituted by 1-3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, quaternary amino, —SO₃H, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl)or multiple condensed rings (e.g., indolizinyl, benzothiazolyl, orbenzothienyl).

Examples of heteroaryls include, but are not limited to, pyrrole,imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,indolizine, isoindole, indole, indazole, purine, quinolizine,isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline,quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine,acridine, phenanthroline, isothiazole, phenazine, isoxazole,phenoxazine, phenothiazine, imidazolidine, imidazoline, tetrazole andthe like as well as N-alkoxy-nitrogen containing heteroaryl compounds.

The term “heteroaralkyl” refers to a heteroaryl group covalently linkedto an alkylene group, where heteroaryl and alkylene are defined herein.“Optionally substituted heteroaralkyl” refers to an optionallysubstituted heteroaryl group covalently linked to an optionallysubstituted alkylene group. Such heteroaralkyl groups are exemplified by3-pyridylmethyl, quinolin-8-ylethyl, 4-methoxythiazol-2-ylpropyl, andthe like.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “heterocyclyl” refers to a monoradical saturated or partiallyunsaturated group having a single ring or multiple condensed rings,having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, forexample 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus,and/or oxygen within the ring wherein said sulfur and phosphorous can bein the following oxidation states —S—, —S(O)—, —S(O)₂— and —P—, —P(O)—,and —P(O)₂—, respectively.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, and for example 1 to 3 substituents, selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, phosphate, thiocarbonyl,aminosulfinyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, quaternary amino,—SO₃H, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1-3 substituentschosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy,alkoxy, halogen, CF₃, amino, substituted amino, cyano, quaternary amino,—SO₃H, and —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0,1 or 2. Heterocyclic groups can have a single ring or multiple condensedrings. Preferred heterocyclics include, but are not limited to,tetrahydrofuranyl, morpholino, and piperidinyl.

The term “thiol” refers to the group —SH.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfinyl” refers to a group —S(O)R, in which R is alkyl, aryl,or heteroaryl. “Substituted sulfinyl” refers to a group —S(O)R, in whichR is substituted alkyl, substituted aryl, or substituted heteroaryl, asdefined herein.

The term “sulfonyl” refers to a group —S(O)₂R, in which R is alkyl,aryl, or heteroaryl. “Substituted sulfonyl” refers to a group —S(O)₂R,in which R is substituted alkyl, substituted aryl, or substitutedheteroaryl, as defined herein.

The term “keto” refers to a group —C(O)—. The term “thiocarbonyl” or“sulfinyl” refers to a group C(S)—. The term “carboxy” refers to a group—C(O)—OH.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

The term “compound of Formula I” is intended to encompass the compoundsof the invention as disclosed, and the pharmaceutically acceptablesalts, pharmaceutically acceptable esters, and prodrugs of suchcompounds. Additionally, the compounds of the invention may possess oneor more asymmetric centers, and can be produced as a racemic mixture oras individual enantiomers or diastereoisomers. The number ofstereoisomers present in any given compound of Formula I depends uponthe number of asymmetric centers present (there are 2^(n) stereoisomerspossible where n is the number of asymmetric centers). The individualstereoisomers may be obtained by resolving a racemic or non-racemicmixture of an intermediate at some appropriate stage of the synthesis,or by resolution of the compound of Formula I by conventional means. Theindividual stereoisomers (including individual enantiomers anddiastereoisomers) as well as racemic and non-racemic mixtures ofstereoisomers are encompassed within the scope of the present invention,all of which are intended to be depicted by the structures of thisspecification unless otherwise specifically indicated.

“Isomers” are different compounds that have the same molecular formula.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer,the stereochemistry at each chiral carbon may be specified as either Ror S. Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) in which they rotate the plane of polarized light at thewavelength of the sodium D line.

The term “therapeutically effective amount” refers to that amount of acompound of Formula I that is sufficient to effect treatment, as definedbelow, when administered to a mammal in need of such treatment. Thetherapeutically effective amount will vary depending upon the subjectand disease condition being treated, the weight and age of the subject,the severity of the disease condition, the manner of administration andthe like, which can readily be determined by one of ordinary skill inthe art.

The term “treatment” or “treating” means any treatment of a disease in amammal, including:

-   -   (i) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   (ii) inhibiting the disease, that is, arresting the development        of clinical symptoms; and/or    -   (iii) relieving the disease, that is, causing the regression of        clinical symptoms.

In many cases, the compounds of this invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. The term “pharmaceuticallyacceptable salt” refers to salts that retain the biologicaleffectiveness and properties of the compounds of Formula I, and whichare not biologically or otherwise undesirable. Pharmaceuticallyacceptable base addition salts can be prepared from inorganic andorganic bases. Salts derived from inorganic bases, include by way ofexample only, sodium, potassium, lithium, ammonium, calcium andmagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl) amines, tri(substituted alkenyl) amines,cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines,disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines,aryl amines, diaryl amines, triaryl amines, heteroaryl amines,diheteroaryl amines, triheteroaryl amines, heterocyclic amines,diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amineswhere at least two of the substituents on the amine are different andare selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic,and the like. Also included are amines where the two or threesubstituents, together with the amino nitrogen, form a heterocyclic orheteroaryl group.

Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine,tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

A compound that is an agonist with high intrinsic efficacy evokes themaximal effect of which the biological system is capable. Thesecompounds are known as “full agonists”. They are able to elicit themaximum possible effect without occupying all the receptors, if theefficiency of coupling to the effector process is high. In contrast,“partial agonists” evoke a response but cannot evoke the maximalresponse of which the biological system is capable. They may havereasonable affinity but low intrinsic efficacy.

The term “therapeutically effective amount” refers to that amount of acompound of Formula I that is sufficient to effect treatment, as definedbelow, when administered to a mammal in need of such treatment. Thetherapeutically effective amount will vary depending upon the subjectand disease condition being treated, the weight and age of the subject,the severity of the disease condition, the manner of administration andthe like, which can readily be determined by one of ordinary skill inthe art.

The term “coronary artery disease” means a chronic disease in whichthere is arteriosclerosis of the coronary arteries.

The term “atherosclerosis” refers to a form of arteriosclerosis in whichdeposits of yellowish plaques containing cholesterol, lipoid material,and lipophages are formed within the intima and inner media of large andmedium-sized arteries.

The term “treatment” or “treating” means any treatment of a disease in amammal, including:

-   -   (i) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   (ii) inhibiting the disease, that is, arresting the development        of clinical symptoms; and/or    -   (iii) relieving the disease, that is, causing the regression of        clinical symptoms.

Nomenclature

The compounds of the invention are numbered according to the followingscheme:

The naming and numbering of the compounds of the invention isillustrated with a representative compound of Formula I:

in which A and D are phenyl, R¹ and R² are methyl, R³ is 3-methoxy, R⁴,R⁵, R⁶, and R⁷ are hydrogen, R⁸ is1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl, which is named2-((12aS,6aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol.In the above structure, the BC cis ring juncture is indicated as(12aS,6aR) as drawn, however, it is understood that this also represents(12aR,6aS) cis compound, since these compounds are racemic. When aspecific enantiomer is intended the naming convention will be indicated,for example, as (12aS*, 6aR*).

DETAILED DESCRIPTION OF THE INVENTION Synthesis of the Compounds ofFormula I

The compounds of Formula I in which X is oxygen may be prepared as shownin Reaction Scheme I.

Step 1

In general, the compound of formula (1) is reacted with a compound offormula (1) in a polar solvent, for example N,N-dimethylformamide, inthe presence of a base, preferably an inorganic base, for example,potassium carbonate, at room temperature, for about 12-72 hours,preferably about 48 hours. When the reaction is substantially complete,the product of formula (3) is isolated by conventional means and usedwith no further purification.

Step 2

In general, the compound of formula (3) is reacted with a compound offormula (4) in an inert solvent, for example acetonitrile, in thepresence of a catalytic amount of a strong acid, for example,trifluoroacetic acid. The reaction is conducted at room temperature orat about 50-100° C., preferably about 80° C., for about 4-24 hours,preferably about 12 hours. When the reaction is substantially complete,the product of Formula I is isolated using conventional means, forexample, chromatography on silica gel or neutral alumina, and may beused without further purification.

Conventional heating is required for the preparation of the compound ofFormula III in which R⁶ is optionally substituted less hindered loweralkyl, —C(O)R¹², or S(O)₂R¹². As before, the compound of formula (3) isgenerally reacted with the compound of formula (2) in an inert solvent,such as DMF, in the presence of a catalytic amount of a strong acid, forexample, trifluoroacetic acid. The reaction is conducted at about50-100° C., preferably about 90° C., for about 4-48 hours, preferablyabout 24 hours, and then isolated and purified as discussed above.

Microwave irradiation is useful for the preparation of the compound ofFormula I in which R⁶ is an optionally substituted hindered substituent,for example a cyclohexyl group. The compounds of formula (2) and (3) aresubjected to the same reaction conditions as before, however, thereaction is conducted using microwave irradiation at about 100-220° C.,preferably about 180° C., for about 5-60 minutes, preferably about 20minutes.

Further Substitution on the D Ring

In those instances where R⁸ or R²⁰ is a halogen, preferably bromo, the Dring can be further substituted by carrying out a Suzuki coupling, asshown in Reaction Scheme II.

As shown above, the compound of Formula I in which R⁸ is bromo isreacted with an appropriately substituted boronic acid derivative, forexample with 4-fluorophenylboronic acid, in an aqueous solvent mixture,for example acetonitrile/aqueous sodium carbonate. The reaction istypically conducted in the presence of a catalyst, for exampledichlorobis-(triphenylphosphine) palladium(II), at a temperature ofabout 150° C., under irradiation in a microwave, for about 10 minutes toabout 1 hour. When the reaction is substantially complete, the productof Formula I is isolated by conventional means, for example bypartitioning the crude reaction mixture between ethyl acetate/aqueoussodium hydroxide, separating the organic layer, removing the solventunder reduced pressure, followed by chromatography of the residue,preferably preparatory TLC.

In those instances where the R⁷, R⁸, or R²⁰ moiety has a terminalcarboxylic acid group, the D ring can be further substituted to providean aminocarbonyl linking moiety as shown in Reaction Scheme III.

In Reaction Scheme III, R⁸ is depicted as the D ring substituent havingthe terminal acidic moiety and R^(8′) is the portion of R⁸ linking theterminal acid group with the D ring. The acidic compound of formula I isreacted with a primary or secondary amine in a polar solvent, forexample N,N-dimethylformamide (DMF), in the presence of a couplingreagent, for example, EDCI, and a base, preferably an organic base, forexample, triethylamine, at room temperature, for about 12-72 hours,preferably about 48 hours. When the reaction is substantially complete,the product of formula I is isolated by conventional means, for example,aqueous work up and chromatography on silica gel, and may be usedwithout further purification.

It will be appreciated by those of skill in the art that a terminalcarbocylic acid group can be easily achieved by hydrolyzing an analogouscompound having terminal ethyl ester.

Terminal R⁷, R⁸, or R²⁰ cyano groups can also be further substituted toprovide a tetrazole substituent as shown in Reaction Scheme IV.

In this method, the cyano compound of formula I is reacted with sodiumazide and zinc bromide in a polar solvent, for example DMF. The reactionmixture is subjected to microwave irradiation at 220° C. for 30 minutesto an hour and then cooled to room temperature. When the reaction issubstantially complete, the product of formula I is isolated byconventional means, for example, aqueous work up and chromatography onsilica gel, and may be used without further purification.

Terminal R⁷, R⁸, or R²⁰ thio groups can also be further substituted toprovide a sulfonyl substituent as shown in Reaction Scheme V.

In this method, a cooled (0° C.) solution of the R⁸ thio compound offormula I in anhydrous chloroform is reacted with 3-chloroperoxybenzoicacid. The reaction mixture is typically stirred at 0° C. for 5-10minutes and then the ice bath removed. After about 30 minutes to an hourof stirring at room temperature, the reaction is substantially completedand the product of formula I is isolated by conventional means.Generally isolation and purification may be accomplished by filteringthrough a layer of dry sodium sulfate (top) and silica gel (bottom),followed aqueous work up and chromatography on silica gel.

It will be appreciated that the above substitutions and modification canbe made to the D ring prior to formation of the compound of formula I,i.e., by modification of the compound of formula (4) prior to reactionwith the formula (3) compound in Step 2 of Reaction Scheme I. An exampleof this is presented in Reaction Scheme VI.

Step 1

In general, an acidic variant of the formula (4) compound, compound (4a)is reacted with an amine of formula (5) in a polar solvent, for exampleDMF, in the presence of a coupling reagent, for example, EDCI, and abase, preferably an organic base, for example, triethylamine, at roomtemperature, for about 12-72 hours, preferably about 48 hours. When thereaction is substantially complete, the aminocarboxy substituted productof formula (4b), also a formula (4) compound, is isolated byconventional means, for example, aqueous work up and chromatography onsilica gel, and may be used without further purification.

Step 2

The compound of formula (4a) is then reacted with a compound of formula(3) in an inert solvent, for example DMF, in the presence of a catalyticamount of a strong acid, for example, trifluoroacetic acid. The reactionis conducted at room temperature or at about 50-100° C., preferablyabout 80-90° C., or under microwave irradiation at about 150-240° C.,preferably about 180° C., for about 10-40 minutes, preferably about 20minutes. When the reaction is substantially complete, the product ofFormula I is isolated using conventional means, for example,chromatography on silica gel or reverse-phase HPLC, and may be usedwithout further purification.

Further Substitution on the A Ring

In those instances where R³, R⁴ or R⁵ is a halogen, preferably iodo orbromo, the A ring can be further substituted by carrying out a Heckreaction, or as shown in Reaction Scheme VII.

As shown above, the compound of Formula I in which R⁴ is iodo is reactedwith dimethylacrylamide in an inert solvent, for exampleN,N-dimethylformamide, in the presence of a quarternary base, forexample tetrabutylammonium chloride, a catalyst, for examplepalladium(II) diacetate, and a tertiary base, for example triethylamine.The mixture is heated to a temperature of about 60-100° C., for about4-24 hours. When the reaction is substantially complete, the product ofFormula I is isolated by conventional means.

If desired, the acrylamide derivative can then be reduced to anN,N-dimethyl-propanamide derivative by conventional reduction, forexample with a mixture of nickel chloride/sodium borohydride. Thereduction is typically carried out in an aqueous solvent, for examplemethanol/water, at about room temperature.

Alternatively, the A ring can be further substituted by reacting thehalogenated compound with a boronic acid derivative of the desired R⁴substituent, or as shown in Reaction Scheme VIII.

As shown above, the compound of Formula I in which R⁴ is bromo or iodois reacted with an appropriately substituted boronic acid derivative,for example with aromatic boronic acid or heterocyclic boronic acid, inan aqueous solvent mixture, for example dimethoxyethane (DME)/aqueoussodium carbonate. The reaction is typically conducted in the presence ofa catalyst, for example dichlorobis-(triphenylphosphine) palladium(II),at a temperature of about 150° C., under irradiation in a microwave, forabout 10 minutes to about 1 hour. When the reaction is substantiallycomplete, the product of Formula I is isolated by conventional means,for example by filtrating through celite, partitioning the crudereaction mixture between ethyl acetate/aqueous lithium hydroxide,separating the organic layer, removing the solvent under reducedpressure, followed by chromatography of the residue, preferablypreparatory TLC or reverse phase HPLC.

Utility, Testing and Administration General Utility

The compounds of Formula I stimulate the expression of ABCA1 inmammalian cells, and may thereby increase cholesterol efflux and raiseHDL levels in plasma. Thus, the compounds of Formula I are useful fortreating conditions treatable by increasing ABCA1 expression including,but not limited to, coronary artery disease, dyslipidiemia and metabolicsyndrome and may also be useful in treating other conditions related tohigh cholesterol/low HDL levels in mammals.

Testing

Activity testing is conducted as described in those patents and patentapplications referenced above, and in the Examples below, and by methodsapparent to one skilled in the art.

Pharmaceutical Compositions

The compounds of Formula I are usually administered in the form ofpharmaceutical compositions. This invention therefore providespharmaceutical compositions that contain, as the active ingredient, oneor more of the compounds of Formula I, or a pharmaceutically acceptablesalt or ester thereof, and one or more pharmaceutically acceptableexcipients, carriers, including inert solid diluents and fillers,diluents, including sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants. Thecompounds of Formula I may be administered alone or in combination withother therapeutic agents. Such compositions are prepared in a mannerwell known in the pharmaceutical art (see, e.g., Remington'sPharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17^(th)Ed. (1985) and “Modern Pharmaceutics”, Marcel Dekker, Inc. 3^(rd) Ed.(G. S. Banker & C. T. Rhodes, Eds.).

Administration

The compounds of Formula I may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parental, particularly by injection. Theforms in which the novel compositions of the present invention may beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof Formula I in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral administration is another route for administration of the compoundsof Formula I. Administration may be via capsule or enteric coatedtablets, or the like. In making the pharmaceutical compositions thatinclude at least one compound of Formula I, the active ingredient isusually diluted by an excipient and/or enclosed within such a carrierthat can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, in can be a solid, semi-solid,or liquid material (as above), which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, for example, up to 10% by weightof the active compound, soft and hard gelatin capsules, sterileinjectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds of Formula I are effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount.Preferably, for oral administration, each dosage unit contains from 10mg to 2 g of a compound of Formula I, more preferably from 10 to 700 mg,and for parenteral administration, preferably from 10 to 700 mg of acompound of Formula I, more preferably about 50-200 mg. It will beunderstood, however, that the amount of the compound of Formula Iactually administered will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLE 1 Preparation of a Compound of Formula (3) A. Preparation of aCompound of Formula (3) in which A is Phenyl, R¹ and R² are Methyl, R³is 2-Methoxy, R⁴ and R⁵ are Hydrogen, and X is Oxygen

To a solution of 2-hydroxy-5-methoxybenzaldehyde (7.6 g, 50 mmol) in dryN,N-dimethylformamide (100 mL) was added potassium carbonate (10.4 g),followed by 1-bromo-3-methylbut-2-ene (10.0 g, 67 mmol). The mixture wasstirred at room temperature for 48 hours and ethyl acetate added.Sufficient 1M hydrochloric acid was cautiously added to neutralize thebase, and the organic layer was washed with water three times, followedby brine, and dried over magnesium sulfate. The mixture was filtered,and solvent removed from the filtrate under reduced pressure, to provide5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde.

¹H NMR (400 MHz, CDCl₃) δ 1.73(s, 3H), 1.79 (s, 3H), 3.8 (s, 3H), 4.6(d, J=6.6 Hz, 2H), 5.48 (m, 1H), 6.96 (d, J=9.3 Hz, 1H), 7.12 (dd,J=9.0, 3.5 Hz, 1H), 7.52 (d, J=3.5 Hz, 1H), 10.45 (s, 1H) B. Preparationof a Compound of Formula (3), Varying R¹, R², R³, and R⁴

Similarly, following the procedure of 1A above, but replacing2-hydroxy-5-methoxybenzaldehyde with other formula (1) compounds orreplacing 1-bromo-3-methylbut-2-ene with other formula (2) compounds,the following compounds of formula (3) were prepared:

-   2-(3-methylbut-2-enyloxy)benzaldehyde;-   5-bromo-2-(3-methylbut-2-enyloxy)benzaldehyde;-   3-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde;-   6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde;-   3-ethoxy-2-(3-methylbut-2-enyloxy)benzaldehyde;-   3-methyl-2-(3-methylbut-2-enyloxy)benzaldehyde;-   4-carboxy-2-(3-methylbut-2-enyloxy)benzaldehyde;-   3-fluoro-2-(3-methylbut-2-enyloxy)benzaldehyde;-   5-trifluoromethyloxy-2-(3-methylbut-2-enyloxy)benzaldehyde;-   3-methoxy-5-bromo-2-(3-methylbut-2-enyloxy)benzaldehyde;-   4-methoxy-6-bromo-2-(3-methylbut-2-enyloxy)benzaldehyde;-   3-methoxy-5-chloro-2-(3-methylbut-2-enyloxy)benzaldehyde;-   3,5-difluoro-2-(3-methylbut-2-enyloxy)benzaldehyde;-   3,5-dichloro-2-(3-methylbut-2-enyloxy)benzaldehyde;-   2,3-bis(3-methylbut-2-enyloxy)benzaldehyde;-   3-methylbut-2-enyl 3-formyl-4-(3-methylbut-2-enyloxy)benzoate;-   3-methylbut-2-enyl 4-formyl-3-(3-methylbut-2-enyloxy)benzoate;-   2-(cinnamyloxy)-6-methoxybenzaldehyde; and-   2-(3-methylbut-2-enyloxy)-3,6-dimethylbenzaldehyde.

C. Preparation of a Compound of Formula (3), Varying R¹, R², R³, R⁴, R⁵,and X

Similarly, following the procedure of 1A above, but replacing2-hydroxy-5-methoxybenzaldehyde with other formula (1) compounds orreplacing 1-bromo-3-methylbut-2-ene with other formula (2) compounds,the following compounds of formula (3) are prepared.

-   5-methoxy-2-(3-methylbut-2-enylthio)benzaldehyde;-   2-(3-methylbut-2-enylthio)benzaldehyde-   5-bromo-2-(3-methylbut-2-enylthio)benzaldehyde;-   3-methoxy-2-(3-methylbut-2-enylthio)benzaldehyde;-   6-methoxy-2-(3-methylbut-2-enylthio)benzaldehyde;-   3-ethoxy-2-(3-methylbut-2-enylthio)benzaldehyde;-   3-methyl-2-(3-methylbut-2-enylthio)benzaldehyde;-   4-carboxy-2-(3-methylbut-2-enylthio)benzaldehyde;-   3-fluoro-2-(3-methylbut-2-enylthio)benzaldehyde;-   5-trifluoromethyloxy-2-(3-methylbut-2-enylthio)benzaldehyde;-   3-methoxy-5-bromo-2-(3-methylbut-2-enylthio)benzaldehyde;-   4-methoxy-6-bromo-2-(3-methylbut-2-enylthio)benzaldehyde;-   3-methoxy-5-chloro-2-(3-methylbut-2-enylthio)benzaldehyde;-   3,5-difluoro-2-(3-methylbut-2-enylthio)benzaldehyde;-   3,5-dichloro-2-(3-methylbut-2-enylthio)benzaldehyde;-   2,3-bis(3-methylbut-2-enylthio)benzaldehyde;-   3-methylbut-2-enyl 3-formyl-4-(3-methylbut-2-enylthio)benzoate; and-   3-methylbut-2-enyl 4-formyl-3-(3-methylbut-2-enylthio)benzoate.

D. Preparation of a Compound of Formula (3) Varying A, R¹, R², R³, R⁴,R⁵, and X

Similarly, following the procedure of 1A above, but replacing2-hydroxy-5-methoxybenzaldehyde with other formula (1) compounds orreplacing 1-bromo-3-methylbut-2-ene with other formula (2) compounds,other compounds of formula (3) are prepared.

EXAMPLE 2 Preparation of a Compound of Formula (3) A. Preparation of aCompound of Formula (3) in which A is Phenyl, R¹ is Methyl, R² is3-Methylbut-2-enyl R³ is 2-Methoxy, R⁴ and R⁵ are Hydrogen, and X isOxygen

To a solution of 2-hydroxy-6-methoxybenzaldehyde (4.72 g, 30.43 mmol) indry DMF (50 ml) was added geranyl bromide (7.5 g, 33.50 mmol) followedby solid potassium carbonate (5.5 g, 39.86 mmol). The mixture wasstirred at room temperature for 48 h. The suspension was filteredthrough a layer of dry sodium sulfate (top) and silica gel (bottom),washed with 200 ml ethyl acetate and decanted into a separatory funnel.The mixture was washed sequentially with aqueous ammonium chloride,water (twice), brine, and the organic phase was dried over Na₂SO4. Thesolution was concentrated in vacuo on a rotovap. The brown gel materialwas then purified by chromatography via silica gel using 8:2hexanes:ethyl acetate eluent to provide2-((E)-3,7-dimethylocta-2,6-dienyloxy)-6-methoxybenzaldehyde as paleyellow oil.

¹H NMR (400 MHz, CDCl₃) δ 10.56 (s, 1H); 7.47 (t, aromatic 1H, J=8.60Hz); 6.604 (d, 1H, J=8.22 Hz); 6.59 (d, 1H, J=8.22 Hz); 5.51 (td, 1H,J=6.65 and 1.17 Hz); 5.11 (m, 1H); 4.67 (d, 2H, J=6.65 Hz); 3.95 (s,3H); 2.16 (m, 4H); 1.50-1.80 (s, 9H).

B. Preparation of a Compound of Formula (3), Varying R¹, R², R³, and R⁴

Similarly, following the procedure of 2A above, but replacing2-hydroxy-5-methoxybenzaldehyde with other formula (1) compounds orreplacing geranyl bromide with other formula (2) compounds, othercompounds of formula (3) are prepared.

EXAMPLE 3 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which A and D are Phenyl, R¹ and R² are Methyl,R³ is 3-Methoxy, R⁴, R⁵, R⁶, R⁷ and R⁸ are Hydrogen, R²⁰ is1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen

A solution of 5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde (1.1 g, 5mmol), 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.3 g, 5mmol) and a catalytic amount of trifluoroacetic acid in acetonitrile (15ml) was heated at 80° C. for 12 hours. After cooling, the solvent wasremoved under reduced pressure, and the residue chromatographed onsilica gel (150 g), eluting with 30% ethyl acetate/hexanes, providing1,1,1,3,3,3-hexafluoro-2-(2-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol(as a 1:1 mixture of cis/trans isomers).

B. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 3A above, but replacing5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3)compounds or replacing2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol with other compoundsof formula (4), the following compounds of Formula I were prepared:

-   2-(2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((6aS,12aR)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((12aS,6aS)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)acetic    acid;-   2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   methyl    2-bromo-10-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylate;-   1,1,1,3,3,3-hexafluoro-2-(2-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   2-[7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-[(12aS,6aS)-7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;-   3-methylbut-2-enyl    (6aS,12aR)-9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;-   3-methylbut-2-enyl    9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;-   3-methylbut-2-enyl    7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate;-   3-methylbut-2-enyl    7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate;-   7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylic    acid;-   3-methylbut-2-enyl    9-(dihydroxyboramethyl)-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate;-   7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylic    acid;-   9-(dihydroxyboramethyl)-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinoline-3-carboxylic    acid;-   1,1,1,3,3,3-hexafluoro-2-(4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   4-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;-   4-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;-   2-(4-ethoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   1,1,1,3,3,3-hexafluoro-2-(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   2-[7,7-dimethyl-4-(3-methylbut-2-enyloxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)acetic    acid;-   3-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)propanoic    acid;-   3-((12aR,6aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)propanoic    acid;-   4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS)-4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   2-((6aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   (6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   4-ethoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1-(4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;-   1-(1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;-   1-methoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   (6aS,12aR)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aS)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (6aS,12aR)-9-fluoro-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylic    acid;-   4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   1,1,1,3,3,3-hexafluoro-2-(4-fluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   ((6aS,12aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-9-fluoro-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-9-ethoxy-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylic    acid;-   10-(1H-1,2,3,4-tetraazol-5-yl)(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   ((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;-   amino(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione;-   {[(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]sulfonyl}methylamine;-   methylethyl    3-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;-   methylethyl    3-(4-methoxy-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinolin-9-yl)benzoate;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-10-carbonitrile;-   2-((6aS,12aR)-1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((6aS,12aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((12aR,6aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2,4-difluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2,4-dichloro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-chloro-4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((6aS,12aR)-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3-thiadiazol-4-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;    and-   1-methoxy-7,7-dimethyl-9-(4-methyl(1,2,4-triazol-3-yl))-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline.-   9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   2-((12aS,6aR)-4-methoxy-7,7-dimethyl-2-phenyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   1-bromo-9-ethoxy-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1-bromo-4-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1-(1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;-   1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide;-   amino(1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione;-   1-bromo-4-methoxy-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-9-bromo-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aS)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   9-(tert-butyl)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   {[(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]sulfonyl}methylamine;-   diethoxy[(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]phosphino-1-one;-   [(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]diethoxyphosphino-1-one;-   1-(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-2-methoxybenzene;-   1-(4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one;-   4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS)-4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   4-fluoro-9-(2-methoxyphenyl)-7,7-dimethyl-7,12-dihydro-6H-chromeno[4,3-b]quinolin-12-ol;-   (2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))[(4-methylphenyl)sulfonyl]amine;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(2-methyl(1,3-thiazol-4-yl))-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   12aS,6aR)-1-methoxy-7,7-dimethyl-9-pyrazol-3-yl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   ethyl    2-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)-1,3-oxazole-4-carboxylate;-   (6aS,12aR)-7-methoxy-13,13-dimethyl-6,13,12a,6a-tetrahydrobenzothiazolo[6,7-b]chromano[3,4-e]pyridine;-   (6aS,12aR)-7-methoxy-13,13-dimethyl-6,13,12a,6a-tetrahydro-1H-chromano[3,4-e]indazolo[6,7-b]pyridine;-   (6aS,12aR)-7-methoxy-2,13,13-trimethyl-6,13,12a,6a-tetrahydrobenzothiazolo[5,4-b]chromano[3,4-e]pyridine;    and-   (12bS,6aR)-12-methoxy-6,6-dimethyl-6,13,12b,6a-tetrahydrochromano[4,3-b]1,2,5-thiadiazolo[3,4-h]quinoline-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-methylthio-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1,1,1,3,3,3-hexafluoro-2-(1-methoxy-7-phenyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol;-   ((7S,12aS,6aR)-1-methoxy-7-phenyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-N,N-dimethylcarboxamide;-   (7S,12aS,6aR)-1-methoxy-9-morpholin-4-yl-7-phenyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carbonitrile;-   (12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   4-{[(12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl]methyl}-1,4-thiazaperhydroine-1,1-dione;    and-   methyl    (12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylate.-   ethyl    1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-1H-pyrazole-4-carboxylate;-   ethyl    1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylate;-   (6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline;-   (6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline;-   (6aR,12aS)-methyl    2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;-   (6aS,12aS)-methyl    2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;-   (6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;-   diethyl    ((6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;-   (6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;-   diethyl    ((6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;-   (6aR,12aS)-6a,7,12,12a-tetrahydro-N-(2-hydroxyethyl)-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;-   ((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;-   (6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-N,N,7,7-tetramethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;-   ((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;-   ((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;-   ((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;-   ((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;-   ((6aS,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;-   ((6aR,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;    and-   ((6aS,12aS)-4-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone.

C. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 3A above, but replacing5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3)compounds or replacing2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol with other compoundsof formula (4) or (4b), the following compounds of Formula I areprepared:

-   2-(2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol-   2-((6aS,12aR)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((12aS,6aS)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-9-carboxamide:-   1,1,1,3,3,3-hexafluoro-2-(2-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;-   1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;-   2-[7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-[(12aS,6aS)-7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;-   3-methylbut-2-enyl    7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-3-carboxylate-   3-methylbut-2-enyl    7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[3,4-e]quinolino[3,2-c]thiane-2-carboxylate-   7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-3-carboxylic    acid-   1,1,1,3,3,3-hexafluoro-2-(4,7,7-trimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;-   4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-   4-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)-1,4-thiazaperhydroine-1,1-dione;-   4-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)-1,4-thiazaperhydroine-1,1-dione;-   2-(4-ethoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-9-carboxamide-   1,1,1,3,3,3-hexafluoro-2-(1-methoxy-7,7-dimethyl    (7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;-   2-[7,7-dimethyl-4-(3-methylbut-2-enyloxy)(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)acetic    acid;-   4,7,7-trimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-9-carboxamide;-   4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-9-carboxamide;-   4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   4,7,7-trimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane-   (12aS)-4,7,7-trimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane-   1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;-   2-((6aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   (6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   (12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   4-ethoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   1-(4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)ethan-1-one;-   1-(1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)ethan-1-one;-   1-methoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane-9-carboxamide-   (6aS,12aR)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   (12aS,6aS)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   (6aS,12aR)-9-fluoro-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thiane-9-carboxamide-   1,1,1,3,3,3-hexafluoro-2-(4-fluoro-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))propan-2-ol;-   4-methoxy-7,7-dimethyl-9-(methylethoxy)-7,12-dihydro-6H-benzo[e]quinolino[3,2-c]thiin-   9-ethoxy-4-methoxy-7,7-dimethyl-7,12-dihydro-6H-benzo[e]quinolino[3,2-c]thiin-   ((6aS,12aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl    oxy))trifluoromethane;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   (12aS,6aR)-9-fluoro-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   (12aS,6aR)-9-ethoxy-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiin-9-carboxylic    acid-   10-(1H-1,2,3,4-tetraazol-5-yl)(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   ((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl    oxy))trifluoromethane;-   amino(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))methane-1-thione;-   {[(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))methyl]sulfonyl}methylamine;-   methylethyl    3-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)benzoate;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiin-10-carbonitrile-   2-((6aS,12aR)-1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((6aS,12aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((12aR,6aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2,4-difluoro-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2,4-dichloro-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-(2-chloro-4,7,7-trimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   2-((6aS,12aR)-7,7-dimethyl(7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydro-6H,12aH,6aH-benzo[e]quinolino[3,2-c]thian-9-yl)-1,4-thiazaperhydroine-1,1-dione;-   4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;-   (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3-thiadiazol-4-yl)-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane;    and-   1-methoxy-7,7-dimethyl-9-(4-methyl(1,2,4-triazol-3-yl))-7,12,12a,6a-tetrahydro-6H-benzo[e]quinolino[3,2-c]thiane.

D. Preparation of a Compound of Formula I, Varying A, D, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 3A above, but replacing5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3)compounds or replacing2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol with other compoundsof formula (4) or (4b), other compounds of Formula I are prepared.

EXAMPLE 4 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which A and D are Phenyl, R¹ and R² are Methyl,R³ is 2-Methoxy, R⁴, R⁵, R⁶, R⁷ and R⁸ are Hydrogen, R²⁰ is—C(O)NH(CH₂)₂OH, and X is Oxygen

As shown above, to a solution of6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde (220 mg, 1.0 mmol) and4-(1,3-oxazolin-2-yl)phenylamine (162 mg, 1.0 mmol) in anhydrous DMF (10ml) was added trifluoroacetic acid (57 mg, 0.5 mmol). The reactionmixture was stirred at 80° C. for about 2 hours when it wassubstantially done. After cooling, this reaction mixture was taken upwith ethyl acetate (30 ml) and decanted into a separatory funnel. Theorganic phase was washed sequentially with water (30 ml), saturatedammonium chloride (30 ml), brine, and dried over Na₂SO₄. The solutionwas concentrated in vacuo on a rotovap. The crude mixture was thenpurified by reverse phase HPLC using a gradient eluent (2.5 to 97.5%acetonitrile in water) to provide the desired material((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-N-(2-hydroxyethyl)carboxamideas white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, 1H, J=1.75 Hz); 7.40 (dd, 1H, J=9.20,2.10 Hz); 7.21 (t, 1H, J=8.22 Hz); 6.55 (m, 2H); 6.48 (m, 1H); 6.38 (d,1H, J=8.61 Hz); 4.89 (d, 1H, J=3.52 Hz); 4.69 (s, 1H); 4.24 (ddd, 1H,J=10.55, 3.52, 1.17 Hz); 3.95 (s, 3H); 3.85 (m, 2H); 3.63 (m, 2H); 3.57(dd, 1H, J=12.13, 10.96 Hz,); 1.99 (m, 1H); 1.39-1.56 (s, 6H). MS m/z(M+H): 383.06.

B. Preparation of a Compound of Formula I, Varying R²⁰

Similarly, following the procedure of 4A above, but replacing6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3)compounds or replacing 4-(1,3-oxazolin-2-yl)phenylamine with othercompounds of formula (4) or (4b), other compounds of Formula I areprepared.

EXAMPLE 5 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which A and D are Phenyl, R¹, R², and R⁶ areMethyl, R³ is 2-Methoxy, R⁴, R⁵, R⁷ and R⁸ are Hydrogen, R²⁰ is—C(O)OCH₃, and X is Oxygen

To a solution of compound6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde (220 mg, 1.0 mmol) andmethyl 4-(methylamino)benzoate (165 mg, 1.0 mmol) in anhydrous DMF (10ml) was added trifluoroacetic acid (57 mg, 0.5 mmol). The reactionmixture was stirred at 90° C. for about 24 hours when it wassubstantially done. After cooling, this reaction mixture was taken upwith ethyl acetate (30 ml) and decanted into a separatory funnel. Theorganic phase was washed sequentially with water (30 ml), saturatedaqueous sodium bicarbonate (30 ml), ammonium chloride (30 ml), brine,and dried over Na₂SO4. The solution was concentrated in vacuo on arotovap. The resulting yellow gel was then purified by chromatographyvia silica gel using 8:2 hexanes:ethyl acetate eluent to provide 320 mg(87%) of the desired diastereomers methyl(12aS,6aR)-1-methoxy-7,7,12-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylateand methyl(12aS,6aS)-1-methoxy-7,7,12-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylateas pale yellow solid (5.5/1 cis/trans). Reverse phase HPLC using agradient eluent (2.5 to 97.5% acetonitrile in water) provided thedesired product methyl(12aS,6aR)-1-methoxy-7,7,12-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylateas off-white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, 1H, J=1.96 Hz); 7.82 (dd, 1H, J=8.61,1.96 Hz); 7.25 (t, 1H, J=8.22 Hz); 6.64 (d, 1H, J=9.00 Hz); 6.54 (m,2H); 4.95 (s, 1H); 4.30 (dd, 1H, J=10.56, 3.13 Hz); 3.91 (s, 3H); 3.87(m, 1H); 2.84 (s, 1H); 2.00 (m, 1H); 1.41-1.50 (s, 6H). MS m/z (M+H):367.96.

B. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 5A above, but replacing5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3)compounds or replacing methyl 4-(methylamino)benzoate with othercompounds of formula (4) or (4b), the following compounds of Formula Iwere prepared:

-   2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetic    acid;-   2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetic    acid;-   ethyl    2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetate;-   ethyl    2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetate;-   (6aS,12aS)-12-benzyl-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aR,12aS)-12-benzyl-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aR,12aS)-12-ethyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aS,12aS)-12-ethyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   methyl    3-((6aS,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate;-   methyl    3-((6aR,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate;-   (6aR,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aS,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aR,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aS,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;-   (6aS,12aS)-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7,12-trimethyl-6H-chromeno[4,3-b]quinoline;    and-   (6aS,12aS)-3-(benzyloxy)-6a,7,12,12a-tetrahydro-9-methoxy-7,7,12-trimethyl-6H-chromeno[4,3-b]quinoline.

C. Preparation of a Compound of Formula I, Varying A, D, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 5A above, but replacing5-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3)compounds or replacing methyl 4-(methylamino)benzoate with othercompounds of formula (4), other compounds of Formula I are prepared.

EXAMPLE 6 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which A and D are Phenyl, R¹ and R² are Methyl,R⁶ is Cyclohexyl, R³ is 2-Methoxy R⁴, R⁵, R⁷, R⁸, and R²⁰ are Hydrogen,and X is Oxygen

As shown above, to a 3 ml Biotage reaction vial equipped with a stir barwas placed 6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde (220 mg, 1.0mmol), cyclohexylphenylamine (167 mg, 0.95 mmol) in anhydrous DMF (2 ml)and trifluoroacetic acid (57 mg, 0.5 mmol). The reaction vial wascapped, subjected to Personal Chemistry microwave irradiation at 180° C.for 30 minutes. After cooling, this reaction mixture was taken up withethyl acetate (30 ml) and decanted into a separatory funnel. The organicphase was washed sequentially with water (30 ml), saturated aqueoussodium bicarbonate (30 ml), ammonium chloride (30 ml), brine, and driedover Na₂SO₄. The solution was concentrated in vacuo on a rotovap. Theresulting yellow gel was then purified by chromatography via silica gelusing dichloromethane eluent to provide the desired cis-isomer(12aS,6aR)-12-cyclohexyl-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolineand trans-isomer.

¹H NMR for cis-isomer(12aS,6aR)-12-cyclohexyl-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline(400 MHz, CDCl₃) δ 7.15-7.20 (m, 2H); 7.08 (m, 1H); 6.63 (m, 2H); 6.49(d, 1H, J=8.2 Hz); 6.45 (dd, 1H, J=8.2, 0.88 Hz); 4.95 (d, 1H, J=1.1Hz); 4.24 (m, 1H); 3.97 (dd, 1H, J=12.5, 10.6 Hz); 3.86 (s, 3H); 3.25(m, 1H); 2.98 (m, 1H); 1.91 (m, 1H); 1.50-1.60 (m, 5H); 1.36-1.38 (m,7H); 0.70 (t, 3H, J=7.4 Hz). MS m/z (M+H): 377.9.

B. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 6A above, but replacing6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3)compounds or replacing cyclohexylphenylamine with other compounds offormula (4), the following compounds of Formula I were prepared:

-   (6aR,12aS)-6a,7,12,12a-tetrahydro-12-isopropyl-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;    and-   (6aS,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline.

C. Preparation of a Compound of Formula I, Varying A, D, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 6A above, but replacing6-methoxy-2-(3-methylbut-2-enyloxy)benzaldehyde with other formula (3)compounds or replacing cyclohexylphenylamine with other compounds offormula (4), other compounds of Formula I are prepared.

EXAMPLE 7 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which R¹ and R² are Methyl, R³ is 5-Methoxy,R⁴, R⁵, R⁶, R⁷ and R⁸ are Hydrogen, R²⁰ is1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen

To a 5 ml Biotage vial equipped with a stir bar was added(12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline(37 mg, 0.1 mmol), 4-fluorophenyl-boronic acid (17 mg, 0.12 mmol), 125μl of 2N aqueous sodium carbonate solution, and acetonitrile/water (1.5ml/1 ml). The mixture was stirred at room temperature for 2 minutesunder nitrogen, then dichloro bis(triphenylphosphine)palladium (II) (3.5mg, 0.005 mmol) was added, and the vial sealed. The vial was subjectedto irradiation in a chemistry microwave (Emrys Optimizer) for 15 minutesat a temperature of 150° C., then cooled, filtered through celite, andwashed with ethyl acetate (50 ml). The filtrate was washed with 0.5Naqueous sodium hydroxide (30 ml), followed by saturated ammoniumchloride, then brine, and dried over sodium sulfate. After removal ofthe solvent under reduced pressure the residue was dissolved in acetone(50 ml) then subjected to preparative thin layer chromatography, elutingwith ethyl acetate/hexanes (9:1). Evaporation of the solvent provided(12aS,6aR)-9-(4-fluorophenyl)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline.MS 390.06 (M+H).

B. Preparation of a Compound of Formula I, Varying R¹, R², R⁴, R⁵, R⁶,R⁷R⁸, R²⁰, and X

Similarly, following the procedure of 7A above, but replacing(12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolinewith other Formula I compounds or replacing 4-fluorophenyl-boronic acidwith other boronic acid derivates, the following compounds of Formula Iwere prepared:

-   4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzenecarbonitrile;-   (12aS,6aS)-1-methoxy-7,7-dimethyl-9-[4-(trifluoromethyl)phenyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aS)-1-methoxy-7,7-dimethyl-9-phenyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   (12aS,6aR)-9-ethynyl-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   ethyl    4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;-   4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzenesulfonamide;-   [4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]methan-1-ol;-   4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoic    acid;-   ethyl    4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;-   4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzamide;-   (12aS,6aR)-9-(4-fluorophenyl)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;-   1-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-4-methoxybenzene;-   methyl    3-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;-   3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]propanoic    acid; and-   (2E)-3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))phenyl]prop-2-enoic    acid.

C. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 7A above, but replacing(12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolinewith other Formula I compounds or replacing 4-fluorophenyl-boronic acidwith other boronic acid derivates, other compounds of Formula I areprepared.

EXAMPLE 8 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which R¹ and R² are Methyl, R³ is 5-Methoxy,R⁴, R⁵, R⁶, R⁷ and R⁸ are Hydrogen, R²⁰ is1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen

2.68 g of ethyl1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylate,prepared as described in Example 3, was in a solution of 30 mL THF, 30mL of methanol, 30 mL of H₂O. To this solution was added 1.3 g ofLiOH.H₂O. The reaction was stirred at room temperature over the weekend.The solvent was then removed and solution titrated so provide a solidthat was collected by filtration and washed to give the product,1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylicacid.

B. Preparation of a Compound of Formula I in which R¹ and R² are Methyl,R³ is 5-Methoxy, R⁴, R⁵, R⁶, R⁷ and R⁸ are Hydrogen, R²⁰ is1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen

Similarly, following the procedure of 8A above, but replacing ethyl1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylatewith other Formula I compounds, the following compounds of Formula Iwere prepared:

-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic    acid; acid-   2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic    acid.

C. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 8A above, but replacing ethyl1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylatewith other Formula I compounds, other compounds of Formula I areprepared.

EXAMPLE 9 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which R¹ and R² are Methyl, R³ is 5-Methoxy,R⁴, R⁵, R⁶, R⁷ and R⁸ are Hydrogen, R²⁰ is1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen

70 mg of the1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylicacid prepared in Example 8A was placed in 5 ml of dichloromethane alongwith the following:

EDC•HCl 39.7 mg; 1-hydroxybenzotriazole•H₂O 31.7 mg; and Me₂NH•HCl 16.9mg.

The reaction mixture was stirred at room temperature overnight and thenworked up with 1N HCl, died over Na₂SO₄, and then concentrated to yieldthe product,[1-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))pyrazol-4-yl]-N,N-dimethylcarboxamide,as a yellow oil. ¹H NMR confirmed the final product was as intended.

B. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 9A above, but replacing1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylicacid with other Formula I compounds or replacing dimethyl amine withother amine derivates, the following compounds of Formula I wereprepared:

-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone);-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);-   2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone);-   2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone);-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone);-   1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone);-   2-((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic    acid;-   2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone);    and-   2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone.

C. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 9A above, but replacing1-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)pyrazole-4-carboxylicacid with other Formula I compounds or replacing dimethyl amine withother amine derivates, other compounds of Formula I are prepared.

EXAMPLE 10 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which A and D are Phenyl, R¹ and R² are Methyl,R³ is 2-Methoxy, R⁴, R⁵, R⁶, R⁷ and R⁸ are Hydrogen, R²⁰ is2-Nitrophenyl, and X is Oxygen

To a 5 ml Biotage microwave reaction vial was placed a stir bar,3-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzenecarbonitrile(40 mg, 0.1 mmol), sodium azide (20 mg, 0.3 mmol), zinc bromide (46 mg,0.2 mmol) and DMF (2.0 ml). The reaction mixture was capped andsubjected for irradiation at 220° C. for 1 h in a Personal Chemistrymicrowave. The reaction mixture was cooled to room temperature, and 3 mlwater added. It was then filtered through a layer of celite, washed withethyl acetate (3×10 ml), combined organic phase was washed withsaturated aqueous sodium bicarbonate (30 ml), ammonium chloride (30 ml),and brine (30 ml), dried over anhydrous sodium sulfate, concentrated toafford pale yellow solid9-(3-(2H-1,2,3,4-tetraazol-5-yl)phenyl)(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline.MS: m/z (M+H) 439.9.

B. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 10A above, but replacing3-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzenecarbonitrilewith other Formula I compounds, other compounds of Formula I areprepared.

EXAMPLE 11 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which A and D are Phenyl, R¹ and R² are Methyl,R³ is 2-Methoxy, R⁴, R⁵, R⁶, R⁷ and R⁸ are Hydrogen, R²⁰ is2-Nitrophenyl, and X is Oxygen

As shown above, to a cooled (0° C.) solution of(12aS,6aR)-1-methoxy-7,7-dimethyl-9-methylthio-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline(106 mg, 0.31 mmol) in anhydrous chloroform (5 ml) was added3-chloroperoxybenzoic acid (208 mg, 1.2 mmol). The resulting reactionmixture was stirred at 0° C. for 5 minutes and the ice bath was thenremoved. After about 30 minutes of stir at room temperature, thereaction was substantially done. The mixture was filtered through alayer of dry sodium sulfate (top) and silica gel (bottom), washed with50 ml ethyl acetate and decanted into a separatory funnel. The organicphase was washed sequentially with aqueous lithium hydroxide (1N, 5 ml),saturated ammonium chloride (3×10 ml), water, brine, and dried overNa₂SO4. The solution was concentrated in vacuo on a rotovap. The mostlypure yellow solid was then purified by chromatography via silica gelusing 5% MeOH/CHCl₃ eluent to provide(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(methylsulfonyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolineas a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, 1H, J=1.96 Hz); 7.49 (dd, 1H, J=8.41,2.35 Hz); 7.19 (t, 1H, J=8.22 Hz); 6.53 (m, 2H); 6.43 (d, 1H, J=8.61Hz); 4.86 (m, 1H); 4.73 (m, 1H); 4.22 (ddd, 1H, J=10.76, 3.52, 1.56 Hz);3.93 (s, 3H); 3.49 (dd, 1H, J=12.13, 10.56 Hz); 3.01 (s, 3H); 2.00 (m,1H); 1.53-1.61 (s, 6H). MS m/z (M+H): 374.1.

B. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 11A above, the following sulfoxidecompounds of Formula I were prepared:

-   2-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-ylsulfonyl)acetic    acid; and-   (6aR,12aS)-9-(4-fluorophenylsulfonyl)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline.

C. Preparation of a Compound of Formula I, Varying A, D, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 11A above, other sulfoxidecompounds of Formula I are prepared.

EXAMPLE 12 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which R¹ and R² are Methyl, R³ is3-Dimethylacrylamide, R⁴, R⁵, R⁶, R⁷ and R⁸ are Hydrogen, R²⁰ is1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen

To a solution of1,1,1,3,3,3-hexafluoro-2-(2-iodo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol(2.2 g, 3.95 mmol) in dry N,N-dimethylformamide (5 ml) was addedtetrabutylammonium chloride (660 mg, 4 mmols), dimethylacrylamide (309μl), triethylamine (1.4 ml, 10 mmol), followed by palladium diacetate(87 mg, 0.39 mmol). The mixture was heated at 80° C. for 12 hours,cooled, and ethyl acetate was added. The organic layer was washed with1M aqueous hydrochloric acid, water, saturated sodium bicarbonate,brine, and the organic layer was dried over magnesium sulfate. Thesolvent was removed under reduced pressure, and the residue waschromatographed on a silica gel column, eluting with ethyl acetate, toyield(2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}-N,N-dimethylprop-2-enamide.The NMR was satisfactory for the proposed structure.

B. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 12A above, but replacing 4dimethylacrylamide with methyl prop-2-enoate, methyl(2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}prop-2-enoatewas prepared.

C. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 12A above, but replacing1,1,1,3,3,3-hexafluoro-2-(2-iodo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-olwith other Formula I compounds or replacing dimethylacrylamide withother compounds having a terminal carbon-carbon double bond, othercompounds of Formula I are prepared.

EXAMPLE 13 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which R¹ and R² are Methyl, R³ is3-Dimethylpropanamide, R⁴, R⁵, R⁶R⁷ and R⁸ are Hydrogen, R²⁰ is1,1,1,3,3,3-Hexafluoromethanol, and X is Oxygen

To a solution of(2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}-N,N-dimethylprop-2-enamide(100 mg, 0.19 mmol) in methanol/water (6 ml of 5/1) at room temperaturewas added nickel chloride hexahydrate (227 mg, 1.0 mmol), followed bysodium borohydride (18 mg, 0.5 mmol) in portions. The mixture wasstirred for 1 hour at room temperature. The solvent was removed underreduced pressure, diluted with ethyl acetate, and washed with saturatedaqueous sodium bicarbonate, followed by water, and finally brine. Theorganic layer was dried over magnesium sulfate, and solvent removedunder reduced pressure. The residue was dissolved in ethyl acetate andpassed through a portion of silica gel, to provide3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}-N,N-dimethylpropanamide.NMR satisfactory.

B. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 13A above, but replacing

-   (2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}-N,N-dimethylprop-2-enamide    with-   methyl    (2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}prop-2-enoate,    methyl    3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl}propanoate;    was prepared.

C. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 13A above, but replacing

-   (2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}-N,N-dimethylprop-2-enamide    with other Formula I compounds having an unsaturated carbon-carbon    double bond, other compounds of Formula I are prepared.

EXAMPLE 14 Preparation of a Compound of Formula I A. Preparation of aCompound of Formula I in which R¹ and R² are Methyl, R⁴ is Pyrazol-4-ylR³ is 5-Methoxy, R⁵, R⁶, R⁷ and R⁸ are Hydrogen, R²⁰ is Oxazol-5-yl andX is Oxygen

As shown above, to a 3 ml Biotage reaction vial equipped with a stir barwas placed compound(12aS,6aR)-2-bromo-4-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline(22 mg, 0.05 mmol),4,4,5,5-tetramethyl-2-pyrazol-4-yl-1,3,2-dioxaborolane (19 mg, 0.1mmol), 2M aqueous sodium bicarbonate (60 μl, 0.12 mmol), 2 ml mixture ofDME/water/ethanol (7:3:2), and dichloro-(triphenylphosphine)palladium(II) (3 mg, 0.04 mmol). The reaction vial was capped, subjectedto Personal Chemistry microwave irradiation at 140° C. for 20 minutes.After cooling, this reaction mixture was taken up with ethyl acetate (10ml), filtered through a layer of celite, washed with ethyl acetate (2×10ml), and decanted into a separatory funnel. The organic phase was washedsequentially with lithium hydroxide (0.1 N, 20 ml), saturated aqueousammonium chloride (30 ml), brine, and dried over Na₂SO4. The solutionwas concentrated in vacuo on a rotovap. The resulting mixture was thenpurified by chromatography via silica gel using 19:1dichloromethane:methanol eluent to provide the desired compound,(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline,as pale yellow solid.

¹H NMR (400 MHz; CDCl₃) δ 7.83 (d, 1H, J=2.0 Hz); 7.63 (d, 1H, J=2.0Hz); 7.45 (d, 1H, J=2.0 Hz); 7.29 (dd, 1H, J=8.2, 2.0 Hz); 7.13 (s, 1HHz); 7.04 (d, 1H, J=2.0 Hz); 6.98 (d, 1H, J=2.0 Hz); 6.46 (d, 1H, J=8.2Hz); 4.66 (d, 1H, J=3.1 Hz); 4.42 (dd, 1H, J=11.0, 2.7 Hz); 4.19 (s,1H); 3.94 (s, 3H); 3.80 (m, 1H); 2.10 (m, 1H); 1.41-1.55 (s, 6H). MS m/z(M+H): 428.9.

B. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 14A above, but replacing(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinolinewith other compounds of formula I, or replacing4,4,5,5-tetramethyl-2-pyrazol-4-yl-1,3,2-dioxaborolane with otherdioxaborolane derivatives, the following compounds of formula I wereprepared.

-   (6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline;-   (6aR,12aS)-methyl    6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate;-   (6aR,12aS)-methyl    6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5-dimethylisoxazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate;    and-   (6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5-dimethylisoxazol-4-yl)-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline.-   diethyl    (6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;-   diethyl    ((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;    and-   (6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carbonitrile.

C. Preparation of a Compound of Formula I, Varying R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R²⁰, and X

Similarly, following the procedure of 14A above, but replacing(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinolinewith other compounds of formula I, or replacing4,4,5,5-tetramethyl-2-pyrazol-4-yl-1,3,2-dioxaborolane with otherdioxaborolane derivatives, other compounds of Formula I are prepared.

EXAMPLE 15

Several compounds of Formula I prepared as shown in the above procedureswere characterized by NMR and mass spectrometry. For example:

-   2-((6aS,12aR)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol

¹H NMR (400 MHz, CDCl₃) δ 1.36(s, 3H), 1.46 (s, 3H), 2.01 (apparent dt,J=12.1, 3.5 Hz, 1H), 3.4 (bs, 1H), 3.74 (dd, J=12.1, 10.9 Hz, 1H), 4.1(bs, 1H), 4.25 (ddd, J=189, 3.9, 1.6 Hz, 1H), 4.56 (d, J=2.7 Hz, 1H),7.28 (d, J=10.1 Hz, 1H), 7.32 (dd, J=8.6, 2.3 Hz, 1H), 7.36 (d, J=2.3Hz, 1H), 7.45 (d, J=1.5 Hz, 1H)

-   2-((12aS,6aS)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol;

¹H NMR (400 MHz, CDCl₃) δ 1.21(s, 3H), 1.48 (s, 3H), 2.06 (ddd, J=10.9,10.9, 3.1 Hz, 1H), 3.92 (t, J=10.9 Hz, 1H), 4.45 (d, J=10.5 Hz, 1H),4.46 (bs, 1H), 4.5 (dd, J=10.9, 3.2 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H),6.78 (d, J=8.6 Hz, 1H), 7.3 (dd, J=8.6, 2.3 Hz, 1H), 7.34 (d, J=8.6 Hz,1H), 7.42 (d, J=2.3 Hz, 1H), 7.6 (s, 1H)

EXAMPLE 16 mRNA ASSAYS

Modulation of expression of ABCA1 mRNA levels by the compounds of theinvention was determined in the following assays.

Induction of ABC1 in THP-1 cells, was measured using QuantiGene®branched DNA assay as per manufacturer's instructions. Cultures of THP-1were grown to subconfluence in DMEM/10% FBS before replacement withDMEM/BSA and 10 and 3 μM concentrations of the test compounds in DMSOfor 18-20 hours. After treatment of cells with compounds, the cells werelysed with lysis buffer at 37° C. for 20 minutes. The cell lysate andABCA1 specific probe (Genospectra, Inc., Fremont, Calif.) mix were addedto the 96 well capture plate and hybridized at 53° C. for 16-18 hours.The signal was amplified using the amplifier and label probes providedwith the QuantiGene® assay followed by addition of a luminescentalkaline phosphatase substrate, dioxitane. Luminescence was quantifiedin Victor V plate reader.

Step 1

-   -   Cells are lysed to release mRNA in the presence of target        probes. Target mRNA from lysed cells was then captured by        hybridization and transferred to the Capture Plate.

Step 2

-   -   Signal amplification was performed by hybridization of the bDNA        Amplifier and Label Probe.

Step 3

-   -   Addition of chemiluminescence substrate yielded a QuantiGene®        signal proportional to the amount of mRNA present in the sample.

The compounds of the invention demonstrated increased ABCA1 geneexpression in this assay relative to a DMSO control. Table 1 presentsthe relative fold increase in ABCA1 expression over DMSO for variouscompounds of the invention when tested at a concentration of 10 μM.

TABLE 1 ABCA1 Induction Fold Increase over DMSO Vehicle at 10 μM FOLDNUMBER NAME INCREASE 1.2-(2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3- 4.4b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 2.2-((6aS,12aR)-2-bromo-7,7-dimethyl(7,12,12a,6a- 5.1tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 3.2-((12aS,6aS)-2-bromo-7,7-dimethyl(7,12,12a,6a- 3.0tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 4.2-(2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3- 2.1b]quinolin-9-yl)acetic acid; 5.2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3- 3.5b]quinoline-9-carboxamide; 6. methyl2-bromo-10-methoxy-7,7-dimethyl-7,12,12a,6a- 1.6tetrahydrochromano[4,3-b]quinoline-9-carboxylate; 7.1,1,1,3,3,3-hexafluoro-2-(2-methoxy-7,7-dimethyl(7,12,12a,6a- 3.1tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol; 8.2-[7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a- 3.0tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol; 9.2-[(12aS,6aS)-7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a- 2.4tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol; 10. 3-methylbut-2-enyl(6aS,12aR)-9-(dihydroxyboramethyl)-7,7- 1.5dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3- carboxylate;11. 3-methylbut-2-enyl 9-(dihydroxyboramethyl)-7,7-dimethyl- 1.77,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate; 12.3-methylbut-2-enyl 7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1- 4.6(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate; 13. 3-methylbut-2-enyl7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1- 3.4(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate; 14.7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]- 3.17,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylic acid; 15.3-methylbut-2-enyl 9-(dihydroxyboramethyl)-7,7-dimethyl- 1.87,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate; 16.7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]- 2.47,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylic acid; 17.9-(dihydroxyboramethyl)-7,7-dimethyl-7,12-dihydro-6H- 1.8chromeno[4,3-b]quinoline-3-carboxylic acid; 18.1,1,1,3,3,3-hexafluoro-2-(4,7,7-trimethyl(7,12,12a,6a- 5.3tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol; 19.4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)-7,12,12a,6a- 5.6tetrahydrochromano[4,3-b]quinoline; 20.4-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a- 6.5tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione; 21. 4-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-5.6 b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione; 22.2-(4-ethoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3- 4.8b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 23.4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3- 6.1b]quinoline-9-carboxamide; 24.1,1,1,3,3,3-hexafluoro-2-(1-methoxy-7,7-dimethyl(7,12,12a,6a- 6.5tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol; 25.2-[7,7-dimethyl-4-(3-methylbut-2-enyloxy)(7,12,12a,6a- 4.0tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol; 26.2-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3- 5.0b]quinolin-9-yl)acetic acid; 27.3-((6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a- 3.3tetrahydrochromano[4,3-b]quinolin-9-yl)propanoic acid; 28.3-((12aR,6aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a- 1.9tetrahydrochromano[4,3-b]quinolin-9-yl)propanoic acid; 29.4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9- 5.8carboxamide; 30.4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3- 5.3b]quinoline-9-carboxamide; 31.4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 5.5 32.(12aS)-4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3- 4.9b]quinoline; 33.1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a- 6.4tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol; 34.2-((6aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a- 4.5tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 35. methyl(2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1- 4.3(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}prop-2-enoate; 36.(2E)-3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1- 5.3(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}-N,N-dimethylprop-2-enamide; 37.(6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a- 8.3tetrahydrochromano[4,3-b]quinoline; 38.(12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a- 7.0tetrahydrochromano[4,3-b]quinoline; 39.3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1- 3.4(trifluoromethyl)ethyl](7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl)}-N,N-dimethylpropanamide; 40. methyl3-{7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1- 2.1(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-2-yl}propanoate; 41.4-ethoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a- 2.1tetrahydrochromano[4,3-b]quinoline; 42.1-(4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3- 3.8b]quinolin-9-yl)ethan-1-one; 43.1-(1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3- 4.1b]quinolin-9-yl)ethan-1-one; 44.1-methoxy-7,7-dimethyl-9-(trifluoromethy;1)-7,12,12a,6a- 2.2tetrahydrochromano[4,3-b]quinoline; 45.1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3- 4.9b]quinoline-9-carboxamide; 46.(6aS,12aR)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a- 4.2tetrahydrochromano[4,3-b]quinoline; 47.(12aS,6aS)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a- 3.6tetrahydrochromano[4,3-b]quinoline; 48.(6aS,12aR)-9-fluoro-4-methoxy-7,7-dimethyl-7,12,12a,6a- 3.7tetrahydrochromano[4,3-b]quinoline; 49.(12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a- 1.7tetrahydrochromano[4,3-b]quinoline-9-carboxylic acid; 50.4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3- 5.0b]quinoline-9-carboxamide; 51.1,1,1,3,3,3-hexafluoro-2-(4-fluoro-7,7-dimethyl(7,12,12a,6a- 7.8tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol; 52.((6aS,12aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a- 9.5tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane; 53.(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 3.5tetrahydrochromano[4,3-b]quinoline; 54.(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a- 4.3tetrahydrochromano[4,3-b]quinoline; 55.(12aS,6aR)-9-fluoro-1-methoxy-7,7-dimethyl-7,12,12a,6a- 2.5tetrahydrochromano[4,3-b]quinoline; 56.(12aS,6aR)-9-ethoxy-1-methoxy-7,7-dimethyl-7,12,12a,6a- 4.8tetrahydrochromano[4,3-b]quinoline; 57.((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a- 6.1tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane; 58.amino(4-methoxy-7,7-dimethyl(7,12,12a,6a- 6.2tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione; 59.{[(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3- 6.1b]quinolin-9-yl))methyl]sulfonyl}methylamine; 60. methylethyl3-(4-methoxy-7,7-dimethyl-7,12,12a,6a- 4.4tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate; 61. methylethyl3-(4-methoxy-7,7-dimethyl-7,12-dihydro-6H- 2.0chromeno[4,3-b]quinolin-9-yl)benzoate; 62.(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)- 10.67,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 63.(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 3.5tetrahydrochromano[4,3-b]quinoline-10-carbonitrile; 64.2-((6aS,12aR)-1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a- 2.5tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 65.2-((6aS,12aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a- 3.2tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 66.2-((12aR,6aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a- 2.5tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 67.2-(2,4-difluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3- 3.3b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 68.2-(2,4-dichloro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3- 2.7b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 69.2-(2-chloro-4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3- 2.6b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 70.2-((6aS,12aR)-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3- 4.0b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol; 71.(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-yl)- 9.57,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 72.4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 8.4tetrahydrochromano[4,3-b]quinolin-9-yl)-1,4-thiazaperhydroine-1,1-dione; 73. (12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3-thiadiazol-4-yl)-8.0 7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; and 74.1-methoxy-7,7-dimethyl-9-(4-methyl(1,2,4-triazol-3-yl))- 7.97,12,12a,6a-tetrahydrochromano[4,3-b]quinoline. 75.9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a- 7.4tetrahydrochromano[4,3-b]quinoline; 76.4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)- 6.07,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 77.2-((12aS,6aR)-4-methoxy-7,7-dimethyl-2-phenyl(7,12,12a,6a- 5.3tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol 78.1-bromo-9-ethoxy-4-methoxy-7,7-dimethyl-7,12,12a,6a- 2.7tetrahydrochromano[4,3-b]quinoline; 79.1-bromo-4-methoxy-7,7-dimethyl-9-(1,3-oxazol-5-yl)-7,12,12a,6a- 4.1tetrahydrochromano[4,3-b]quinoline; 80.1-(1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a- 4.3tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one; 81.1-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a- 1.9tetrahydrochromano[4,3-b]quinoline-9-carboxamide; 82.amino(1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a- 2.0tetrahydrochromano[4,3-b]quinolin-9-yl))methane-1-thione; 83.1-bromo-4-methoxy-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a- 2.7tetrahydrochromano[4,3-b]quinoline; 84.(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5- 8.6ylmethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 85.(12aS,6aR)-9-bromo-1-methoxy-7,7-dimethyl-7,12,12a,6a- 8.0tetrahydrochromano[4,3-b]quinoline; 86.(12aS,6aR)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a- 8.4tetrahydrochromano[4,3-b]quinoline; 87.(12aS,6aS)-9-bromo-4-methoxy-7,7-dimethyl-7,12,12a,6a- 7.4tetrahydrochromano[4,3-b]quinoline; 88.9-(tert-butyl)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 6.8tetrahydrochromano[4,3-b]quinoline; 89.{[(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3- 6.4b]quinolin-9-yl))methyl]sulfonyl}methylamine; 90.diethoxy[(1-methoxy-7,7-dimethyl(7,12,12a,6a- 7.6tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]phosphino-1-one; 91.[(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a- 6.2tetrahydrochromano[4,3-b]quinolin-9- yl))methyl]diethoxyphosphino-1-one;92. 4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 8.7tetrahydrochromano[4,3-b]quinolin-9-yl)benzenecarbonitrile; 93.(12aS,6aS)-1-methoxy-7,7-dimethyl-9-[4-(trifluoromethyl)phenyl]- 6.87,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 94.(12aS,6aS)-1-methoxy-7,7-dimethyl-9-phenyl-7,12,12a,6a- 5.8tetrahydrochromano[4,3-b]quinoline; 95.(12aS,6aR)-9-ethynyl-1-methoxy-7,7-dimethyl-7,12,12a,6a- 4.3tetrahydrochromano[4,3-b]quinoline; 96. ethyl4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 7.6tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate; 97.4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 5.7tetrahydrochromano[4,3-b]quinolin-9-yl)benzenesulfonamide; 98.[4-((12aS,6aS)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 5.2tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]methan-1-ol; 99.(12aS,6aR)-9-(4-fluorophenyl)-4-methoxy-7,7-dimethyl- 1.77,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 100.1-(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a- 3.0tetrahydrochromano[4,3-b]quinolin-9-yl))-2-methoxybenzene; 101.1-(4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3- 4.0b]quinolin-9-yl)ethan-1-one; 102.4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a- 4.2tetrahydrochromano[4,3-b]quinoline; 103.(12aS)-4-fluoro-7,7-dimethyl-9-(methylethoxy)-7,12,12a,6a- 4.0tetrahydrochromano[4,3-b]quinoline; 104.4-fluoro-9-(2-methoxyphenyl)-7,7-dimethyl-7,12-dihydro-6H- 2.9chromeno[4,3-b]quinolin-12-ol; 105.(2-chloro-4-methoxy-7,7-dimethyl(7,12,12a,6a- 3.6tetrahydrochromano[4,3-b]quinolin-9-yl))[(4-methylphenyl)sulfonyl]amine; 106.4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 4.8tetrahydrochromano[4,3-b]quinolin-9-yl)benzoic acid 107. ethyl4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 2.9tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate; 108.4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 4.7tetrahydrochromano[4,3-b]quinolin-9-yl)benzamide; 109.(12aS,6aR)-9-(4-fluorophenyl)-1-methoxy-7,7-dimethyl- 4.17,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 110.(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(2-methyl(1,3-thiazol-4-yl))- 6.07,12,12a,6a-tetrahydrochromano[4,3-b]quinoline; 111.(12aS,6aR)-1-methoxy-7,7-dimethyl-9-pyrazol-3-yl-7,12,12a,6a- 4.7tetrahydrochromano[4,3-b]quinoline; 112.1-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a- 1.7tetrahydrochromano[4,3-b]quinolin-9-yl))-4-methoxybenzene; 113. methyl3-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 1.5tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate; 114.3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a- 2.7tetrahydrochromano[4,3-b]quinolin-9-yl)phenyl]propanoic acid; 115.(2E)-3-[4-((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a- 2.2tetrahydrochromano[4,3-b]quinolin-9-yl))phenyl]prop-2-enoic acid; 116.ethyl 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7- 2.7dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylate; 117.(6aR,12aS)-6a,7,12,12a-tetrahydro-N-(2-hydroxyethyl)-1-methoxy- 8.67,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide; 118.1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H- 4chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic acid;119. ((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H- 7.5chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone; 120.((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H- 4.2chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone; 121.((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H- 3.2chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone; 122.(6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-9- 2.4(methylsulfonyl)-6H-chromeno[4,3-b]quinoline; 123.(6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-N,N,7,7-tetramethyl- 6.56H-chromeno[4,3-b]quinolin-9-carboxamide; 124.2-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H- 3.3chromeno[4,3-b]quinolin-9-ylsulfonyl)acetic acid; 125.((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H- 4.1chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone; 126.((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H- 7.3chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone; 127.((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H- 5.1chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone; 128.((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H- 2.7chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone; 129.((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H- 4.3chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone; 130.((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H- 4.2chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone; 131.2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H- 2chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic acid; 132.((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H- 4.3chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1- yl)methanone;133. ((6aS,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H- 3.8chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1- yl)methanone;134. ((6aR,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H- 5.8chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1- yl)methanone;and 135. ethyl 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7- 6.4dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-1H-pyrazole-4- carboxylate;136. 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H- 4.1chromeno[4,3-b]quinolin-9-yl)-1H-pyrazole-4-carboxylic acid; 137.1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H- 7chromeno[4,3-b]quinolin-9-yl)-N,N-dimethyl-1H-pyrazole-4- carboxamide;138. 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H- 7.4chromeno[4,3-b]quinolin-9-yl)1-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone); 139.((6aS,12aS)-4-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H- 2.8chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1- yl)methanone.140. 1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H- 5.1chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone); 141.1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H- 7.1chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone); 142.2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H- 5chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone); 143.2-((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H- 6.1chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone); 144.1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H- 2.1chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-((4-ethanesulfonylpiperazin-1-yl)methanone); 145.1-((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H- 4.5chromeno[4,3-b]quinolin-9-yl)1-5-methyl-1H-pyrazole-4-((1,1-dione-1,4-thiazaperhydroin-yl)methanone); 146.2-((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H- 8.2chromeno[4,3-b]quinolin-9-yl)oxazole-4-carboxylic acid; 147.2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H- 7chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(4-ethanesulfonylpiperazin-1-yl)methanone); 148.2-((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H- 11chromeno[4,3-b]quinolin-9-yl)oxazole-(4-(1,1-dione-1,4-thiazaperhydroin-yl)methanone); 149.(6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7- 5.5dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline; 150.(6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7- 12.5dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline; 151.(6aR,12aS)-methyl 2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7- 6.3dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate; 152.(6aS,12aS)-methyl 2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7- 6.1dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate; 153.(6aR,12aS)-methyl 6a,7,12,12a-tetrahydro-1-methoxy-7,7,12- 7.4trimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate; 154.2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H- 9.4chromeno[4,3-b]quinolin-12(12aH)-yl)acetic acid; 155.(6aR,12aS)-6a,7,12,12a-tetrahydro-12-isopropyl-1-methoxy-7,7- 2.7dimethyl-6H-chromeno[4,3-b]quinoline; 156.2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H- 7.6chromeno[4,3-b]quinolin-12(12aH)-yl)acetic acid; 157. ethyl2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H- 3.3chromeno[4,3-b]quinolin-12(12aH)-yl)acetate; 158.(6aR,12aS)-12-benzyl-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7- 9.2dimethyl-6H-chromeno[4,3-b]quinoline; 159.(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9- 7.6(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline; 160.(6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9- 4.7(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline; 161.(6aR,12aS)-methyl 6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl- 8.12-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate; 162.(6aR,12aS)-methyl 6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl- 7.72-(3,5-dimethylisoxazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate; and 163.(6aS,12aS)-12-ethyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7- 3.1dimethyl-6H-chromeno[4,3-b]quinoline; 164.(6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7- 5.6dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline; 165.(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5- 7.4dimethylisoxazol-4-yl)-9-(oxazol-5-yl)-6H-chromeno[4,3- b]quinoline.166. (6aR,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7- 12.5dimethyl-6H-chromeno[4,3-b]quinoline; and 167.(6aS,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7- 7.9dimethyl-6H-chromeno[4,3-b]quinoline. 168. diethyl((6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7- 4dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate; 169.(6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7- 9.7dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline; 170. methyl3-((6aS,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H- 2.3chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate; 171. methyl3-((6aR,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H- 2.2chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate; 172.(6aR,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7- 1.7dimethyl-6H-chromeno[4,3-b]quinoline; 173.(6aS,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7- 1.8dimethyl-6H-chromeno[4,3-b]quinoline; 174.(6aR,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7- 1.9dimethyl-6H-chromeno[4,3-b]quinoline; 175.(6aS,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7- 1.5dimethyl-6H-chromeno[4,3-b]quinoline; 176.(6aS,12aS)-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7,12-trimethyl- 2.96H-chromeno[4,3-b]quinoline; 177.1-((6aS,12aS)-6a,7,12,12a-tetrahydro-2-iodo-4-methoxy-7,7- 2.6dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic acid; 178.1-((6aR,12aS)-6a,7,12,12a-tetrahydro-2-iodo-4-methoxy-7,7- 5.1dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylic acid. 179. diethyl((6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7- 5.2dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate; 180. diethyl(6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H- 2.2chromeno[4,3-b]quinolin-9-yl)methylphosphonate; 181. diethyl((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7- 4.9dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate; 182.(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H- 4.6pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carbonitrile.

EXAMPLE 17 In Vivo Mouse Model

To confirm the in vitro activity of compounds that induce ABCA1 geneexpression in vitro and to further profile for acceptablebioavailability, PK and lipogenic activity, compounds were initiallyscreened in a single dose 5 h mouse model. Compounds were prepared assuspensions in 0.75% carboxymethylcellulose/0.1% Tween 80 andadministered by gavage to male mice at a dose of 1-200 mpk along with avehicle control group. Food was removed immediately prior to dosing andthe mice were bled retro-orbitally at 1 h to measure approximate peakplasma drug levels and at necropsy (5 h), by cardiac puncture, tomeasure 5 h drug levels.

EDTA plasma was separated from the blood samples by centrifugation andused for measurement of plasma drug levels by LC-MS. Primary bloodmononuclear cells (PBMC's) were freshly isolated from the packed bloodcells by differential centrifugation. A liver sample was preserved inRNALater (Qiagen) and the whole intestine was rinsed in saline andsnap-frozen in liquid N₂. RNA was isolated from the liver, intestine andPBMC's from individual mice using a Tissuelyzer (Qiagen) and RNAeasy RNApurification kits (Qiagen) with DNAse treatment (Qiagen).

cDNA was prepared from each RNA sample and used to determine theexpression levels of mouse MABCA1, mSREBP1c, mFASN (fatty acid synthase)and mCYc (cyclophilin A). All 4 genes were measured at the same timeusing a quadraplexed Taqman qPCR assay using custom gene-specificprimer-probe sets. Data was normalized to mCYC and gene expression wasexpressed relative to the vehicle treated group (fold). Compounds thatinduced ABCA1 and achieved acceptable plasma concentrations at both 1hand 5h were analyzed in this model at additional concentrations toobtain dose response information.

The compounds of the invention induced expression of ABCA1 in thisassay.

EXAMPLE 18 Cholesterol Efflux

The ability of the compounds of the invention to stimulate cholesterolefflux from cells is determined in the following assay.

RAW 264.7 cells are loaded with cholesterol as described in Smith etal., J. Biol. Chem., 271:30647-30655 (1996). Briefly, semi-confluentcells plated in 48-well dishes are incubated in 0.2 ml of DMEMsupplemented with 4.5 g/L glucose, 0.1 g/L sodium pyruvate and 0.584 g/Lof glutamine, 10% fetal bovine serum, 50 μg/ml acetylated low densitylipoprotein (AcLDL) and 0.5 μCi/ml of [³H]-cholesterol. After 18 hr,cells are washed two times with PBS containing 1% BSA and incubatedovernight (16-18 hours) in DMEM/1% BSA to allow for equilibration ofcholesterol pools. The cells are then rinsed four times with PBS/BSA andincubated for one hour at 37° C. with DMEM/BSA. Efflux medium (DMEM/BSA)containing either albumin alone (control), albumin plus HDL (40 μgprotein/ml), or albumin plus apo A-I (20 μg/ml, Biodesign International,Kennebunk, Me.) is added and the cells are incubated for 4, 24, or 48hours.

Cholesterol efflux is measured by removing the medium, washing the celllayer and extracting the cells. Cellular radioactivity is measured byscintillation counting after solubilization in 0.5 ml of 0.2M NaOH(Smith et al., J. Biol. Chem., 271:30647-30655 (1996)) or extraction inhexane:isopropanol (3:2 v/v) as described in Francis et al., J. Clin.Invest., 96, 78-87 (1995). The labelled phospholipid remaining in themedium is also determined by liquid scintillation counting. The effluxof cholesterol is expressed as the percentage of tritiated lipid countsin the medium over the total tritiated lipid counts recovered from thecells and medium (cpm medium/cpm (medium+lysate)×100).

Cholesterol efflux is also determined in THP-1 cells. Replicate culturesof THP-1 cells are plated in 48 well dishes using the method described(see Kritharides et al Thrombo Vasc Biol 18, 1589-1599,1998). Cells areplated at an initial density of 500,000 cells/well. After addition ofPMA (100 ng/ml), the cultures are incubated for 48 hr at 37 C. Themedium is aspirated and replaced with RPMI-1640 medium containing 2mg/ml of FAFA, 50 μg/ml of acetylated LDL and 3 μCi/ml of radiolabeledcholesterol. After an overnight incubation, the medium is aspirated, thewells washed extensively with PBS. 0.2 ml of RPMI-1640 medium containing2 mg/ml of FAFA is added to each well. The compound of interest areadded to a final concentration of 10 μM. After 4 hr, Apolipoprotein A1(10 μg/ml) is added to some wells and the cultures incubated for 24 hr.The medium is harvested and assayed for radioactivity. The amount ofradioactivity in the cell layer is ascertained by adding 0.2 ml of 2 MNaOH and counting the lysed cells. The percent cholesterol efflux iscalculated as described above.

EXAMPLE 19

The relationship between ABCA1 expression and HDL levels are determinedin the following in vivo assay.

Candidate compounds that increase ABCA1 expression in vitro and arepharmacologically active and available in vivo are administered daily ata predetermined dosage to 7-12 week old male C57B1/6 mice by gavage in0.75% carboxymethylcellulose/0.1% Tween 80 or other pharmaceuticallyacceptable formulation and route of administration. Five hours after thefinal injection, fasted EDTA—plasma and appropriate tissues arecollected for analysis. Plasma lipoproteins levels and HDL cholesterolare measured by FPLC using a Superose 6/30 column and online detectionof the cholesterol in the eluate. In vivo changes in the expression ofABCA1, SREBP1c, FASN and other relevant genes are further confirmed byqPCR of the cDNA's prepared from tissue RNA.

The in vivo efficacy of candidate compounds to induce lipogenesis andincreased triacylglycerol production and storage is evaluated bymeasuring hepatic SREBP1c gene expression by qPCR and plasma and tissuetriacylglycerol concentrations.

A correlation between ABCA1 expression and HDL levels was observed inthis assay.

1. A compound having the structure of Formula I:

wherein: R¹ and R² are independently optionally substituted lower alkyl,optionally substituted aryl, optionally substituted alkenyl, optionallysubstituted heteroaryl, or optionally substituted heterocyclyl; or R¹and R² when taken together with the carbon atom to which they areattached represent a 5 or 6 membered carbocyclic or heterocyclic ring;R³, R⁴ and R⁵ are independently hydrogen, hydroxyl, optionallysubstituted lower alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted lower alkoxy, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, cyano, halo, —SO₂—NR⁹R¹⁰, or —C(O)R¹¹, inwhich R⁹ and R¹⁰ are independently hydrogen, optionally substitutedlower alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, or may joint to form a5 or 6 membered optionally substituted heterocyclic ring, and R¹¹ is —OHor optionally substituted lower alkoxy; R⁶ is hydrogen, optionallysubstituted lower alkyl, optionally substituted cycloalkyl, —C(O)R¹², or—S(O)₂R¹³, in which R¹² is optionally substituted lower alkyl, loweralkoxy or —NR¹⁴R¹⁵, in which R¹³, R¹⁴, and R¹⁵ are independentlyhydrogen, optionally substituted lower alkyl, optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclyl, or R¹⁴ and R¹⁵ may join to form a 5 or 6 memberedoptionally substituted heterocyclic ring; R⁷ is hydrogen, hydroxyl,optionally substituted lower alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted alkoxy,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, or —NR¹⁴R¹⁵; and R⁸ is hydrogen,cyano, optionally substituted lower alkyl, optionally substitutedheterocyclyl, optionally substituted phenyl, —C(O)R¹¹, —C(O)R¹⁴, —SR¹³,—OR¹³, —NR⁹S(S)₂R¹⁰, —NR¹⁴C(O)NR¹⁴R¹⁵, —C(O)NR¹⁴R¹⁵, —CH₂C(O)R¹¹,—S(O)₂R¹³, —B(OH)₂, —C(CF₃)₂OH, —CH₂P(O)(R¹¹)₂, halo, —NHC(O)R,—N[(CH₂)₂]₂SO₂, or —S(O)₂NR⁹R¹⁰; or R⁷ and R⁸ may join together to forman optionally substituted 5 or 6 membered heterocyclic or heteroarylring; R²⁰ is hydrogen, cyano, hydroxyl, halo, optionally substitutedlower alkyl, optionally substituted alkenyl, optionally substitutedalkynyl, optionally substituted alkoxy, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted heterocyclyl,—NR¹⁴R¹⁵, —C(O)R¹, —C(O)R¹⁴, —SR¹⁴, —OR¹⁴, —C(S)R¹¹, C(S)R¹⁴,—NR⁹S(O)₂R¹⁰, —NR¹⁴C(O)NR¹⁴R¹⁴, —C(O)NR¹⁵R¹⁴, —C(S)NR¹⁵R¹⁴R¹⁵,—CH₂C(O)R¹, —S(O)₂R¹³, B(OH)₂, —C(CF₃)₂OH, —CH₂P(O)(R¹¹)₂, —NHC(O)CH₃,—N[(CH₂)₂]₂SO₂, or —S(O)₂ NR⁹R¹⁰; A and D are independently 5 or 6membered monocyclic heterocyclic, monocyclic heteroaryl, or monocyclicaryl rings; and X is oxygen, sulfur, —S(O)—, —S(O)₂— or —NR¹⁶—, in whichR¹⁶ is hydrogen, optionally substituted lower alkyl, optionallysubstituted aryl, —C(O)R¹², or —S(O)₂R¹³.
 2. The compound of claim 1,wherein A and D are both phenyl.
 3. The compound of claim 2, wherein Xis oxygen.
 4. The compound of claim 3, wherein R¹ and R² are bothindependently optionally substituted lower alkyl.
 5. The compound ofclaim 4, wherein R⁵, R⁷, and R⁸ are hydrogen.
 6. The compound of claim5, wherein R⁶ is hydrogen.
 7. The compound of claim 6, wherein R⁴ ishydrogen.
 8. The compound of claim 7, wherein R²⁰ is hydrogen.
 9. Thecompound of claim 8, selected from the group consisting of:4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;(12aS)-4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;(6aS,12aR)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;(12aS,6aS)-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;and(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline.10. The compound of claim 7, wherein R²⁰ is optionally substituted loweralkyl.
 11. The compound of claim 10, selected from the group consistingof:2-(2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol2-((6aS,12aR)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol2-((12aS,6aS)-2-bromo-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol1,1,1,3,3,3-hexafluoro-2-(2-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol2-[7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol2-[(12aS,6aS)-7,7-dimethyl-2-(trifluoromethoxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol3-methylbut-2-enyl7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylate3-methylbut-2-enyl7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-2-carboxylate7,7-dimethyl-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-3-carboxylicacid1,1,1,3,3,3-hexafluoro-2-(4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol2-(4-ethoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol1,1,1,3,3,3-hexafluoro-2-(1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol2-[7,7-dimethyl-4-(3-methylbut-2-enyloxy)(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)]-1,1,1,3,3,3-hexafluoropropan-2-ol2-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)aceticacid1,1,1,3,3,3-hexafluoro-2-(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol2-((6aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol4-ethoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline1-(4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one1-(1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)ethan-1-one1-methoxy-7,7-dimethyl-9-(trifluoromethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline(6aS,12aR)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline(12aS,6aS)-4-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline1,1,1,3,3,3-hexafluoro-2-(4-fluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol(12aS,6aR)-1-methoxy-7,7-dimethyl-9-(methylethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline2-((6aS,12aR)-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol4-methoxy-7,7-dimethyl-9-(1,2,3,4-tetraazol-5-ylmethyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolinediethyl(6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;12. The compound of claim 7, wherein R²⁰ is halogen, acyl, alkoxy, orcyano.
 13. The compound of claim 12, selected from the group consistingof:(6aS,12aR)-9-fluoro-4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;((6aS,12aR)-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;(12aS,6aR)-9-fluoro-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;(12aS,6aR)-9-ethoxy-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline;(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylicacid;((12aS,6aR)-1-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yloxy))trifluoromethane;{[(4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))methyl]sulfonyl}methylamine;methylethyl3-(4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl)benzoate;and(12aS,6aR)-1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-10-carbonitrile.14. The compound of claim 7, wherein R²⁰ is —C(O)NR¹⁴R¹⁵.
 15. Thecompound of claim 14, selected from the group consisting of:2-bromo-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide4-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide4,7,7-trimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide4-ethoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide1-methoxy-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide4-fluoro-7,7-dimethyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxamide(6aR,12aS)-6a,7,12,12a-tetrahydro-N-(2-hydroxyethyl)-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide;((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(morpholino)methanone;((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;(6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-N,N,7,7-tetramethyl-6H-chromeno[4,3-b]quinoline-9-carboxamide;((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone;((6aR,12aS)-6a,7,12,12a-tetrahydro-1-fluoro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-tert-butyl-carboxylate-piperazin-1-yl)methanone;((6aR,12aS)-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;((6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(1,1-dione-1,4-thiazaperhydroin-yl)methanone;((6aR,12aS)-1-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(piperazin-1-yl)methanone;((6aR,12aS)-1-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;((6aS,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;((6aR,12aS)-4-methoxy-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone;and((6aS,12aS)-4-fluoro-6a,7,12,12a-tetrahydro-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)(4-ethanesulfonylpiperazin-1-yl)methanone.16. The compound of claim 7, wherein R²⁰ is optionally substitutedheteroaryl.
 17. The compound of claim 7, wherein R²⁰ is optionallysubstituted heterocycle.
 18. The compound of claim 7, wherein R²⁰ isaryl.
 19. The compound of claim 7, wherein R²⁰ is —SR¹⁴, —SR¹⁵,—S(O)₂R¹³, —C(S)R¹⁴—C(S)NR¹⁴R¹⁵.
 20. The compound of claim 4, whereinR⁴, R⁵, R⁶, R⁷, and R⁸ are hydrogen.
 21. The compound of claim 20,selected from the group consisting of:1,1,1,3,3,3-hexafluoro-2-(1-methoxy-7-phenyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))propan-2-ol4-{[(12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl]methyl}-1,4-thiazaperhydroine-1,1-dionemethyl(12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carboxylate(12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline-9-carbonitrile((7S,12aS,6aR)-1-methoxy-7-phenyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-N,N-dimethylcarboxamide(7S,12aS,6aR)-1-methoxy-9-morpholin-4-yl-7-phenyl-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline(12aS,7R,6aR)-1-methoxy-7-methyl-7-(4-methylpent-3-enyl)-9-(1,3-oxazol-5-yl)-7,12,12a,6a-tetrahydrochromano[4,3-b]quinoline22. The compound of claim 4, wherein R¹ and R² are optionallysubstituted lower alkyl and R⁵, R⁶, R⁷, and R⁸ are hydrogen.
 23. Thecompound of claim 22, selected from the group consisting of: diethyl((6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;diethyl((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;and2-((6aS,12aR)-1-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol2-((6aS,12aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol2-((12aR,6aR)-2-bromo-4-methoxy-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol2-(2,4-difluoro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol2-(2,4-dichloro-7,7-dimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-ol2-(2-chloro-4,7,7-trimethyl(7,12,12a,6a-tetrahydrochromano[4,3-b]quinolin-9-yl))-1,1,1,3,3,3-hexafluoropropan-2-oldiethyl((6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;diethyl((6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;diethyl((6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinolin-9-yl)methylphosphonate;(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carbonitrile;(6aR,12aS)-methyl2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;(6aS,12aS)-methyl2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;(6aR,12aS)-methyl6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate;(6aR,12aS)-methyl6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5-dimethylisoxazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carboxylate;and(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline-9-carbonitrile.(6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;1-((6aS,12aS)-6a,7,12,12a-tetrahydro-2-iodo-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylicacid; and1-((6aR,12aS)-6a,7,12,12a-tetrahydro-2-iodo-4-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-9-yl)-5-methyl-1H-pyrazole-4-carboxylicacid.(6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(1H-tetrazol-5-yl)-6H-chromeno[4,3-b]quinoline;(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-2-(3,5-dimethylisoxazol-4-yl)-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline.(6aR,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline;(6aS,12aS)-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-2-(1H-pyrazol-4-yl)-6H-chromeno[4,3-b]quinoline;(6aR,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline;and(6aS,12aS)-2-bromo-6a,7,12,12a-tetrahydro-4-methoxy-7,7-dimethyl-9-(oxazol-5-yl)-6H-chromeno[4,3-b]quinoline.24. The compound of claim 4, wherein R¹ and R² are optionallysubstituted lower alkyl and R⁴, R, R⁷, R⁸, and R²⁰ are hydrogen.
 25. Thecompound of claim 24, selected from the group consisting of:2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)aceticacid;(6aR,12aS)-6a,7,12,12a-tetrahydro-12-isopropyl-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)aceticacid; ethyl2-((6aS,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetate;ethyl2-((6aR,12aS)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)acetate;(6aS,12aS)-12-ethyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;(6aR,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;and(6aS,12aS)-12-cyclohexyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolinemethyl3-((6aS,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate;methyl3-((6aR,12aR)-6a,7-dihydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinolin-12(12aH)-yl)propanoate;(6aR,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;(6aS,12aS)-12-propyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;(6aR,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;and(6aS,12aS)-12-butyl-6a,7,12,12a-tetrahydro-1-methoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline.26. The compound of claim 4, wherein R¹ and R² are optionallysubstituted lower alkyl and R⁴, R⁵, R⁷, and R⁸ are hydrogen.
 27. Thecompound of claim 26, selected from the group consisting of:(6aS,12aS)-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7,12-trimethyl-6H-chromeno[4,3-b]quinoline;and(6aR,12aS)-12-benzyl-6a,7,12,12a-tetrahydro-1,9-dimethoxy-7,7-dimethyl-6H-chromeno[4,3-b]quinoline;(6aR,12aS)-methyl6a,7,12,12a-tetrahydro-1-methoxy-7,7,12-trimethyl-6H-chromeno[4,3-b]quinoline-9-carboxylate;28. The compound of claim 1, wherein the 12a,6a ring juncture is cis.29. The compound of claim 1, wherein the 12a,6a ring juncture is trans.30. The compound of claim 1, wherein the 12a,6a ring juncture provides asingle enantiomer
 31. A method of treating a disease state or conditionin a mammal that is alleviable by treatment with an agent capable ofincreasing ABCA-1 expression, comprising administering to a mammal inneed thereof a therapeutically effective dose of a compound of claim 1.32. The method of claim 35, wherein the disease state or condition iscoronary artery disease or atherosclerosis.
 33. A method for elevatingserum levels of HDL cholesterol in a mammal, comprising administering toa mammal in need thereof a therapeutically effective dose of a compoundof claim
 1. 34. A method for promoting cholesterol efflux from cells ina mammal, comprising administering to a mammal in need thereof atherapeutically effective dose of a compound of claim
 1. 35. Apharmaceutical composition comprising at least one pharmaceuticallyacceptable excipient and a therapeutically effective amount of acompound of claim 1.